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METHODS OF USING (+)-1,4-DIRYDRO-7-1(3S,48)-3-METHOXY-4-(METHYLAIVLINO)-1-
PYRROLIDINYLl-4-0X0-1-(2-THIAZOLYL)-1,8-NAPHTHYRIDINE-3-CARBOXYLIC
ACID FOR TREATMENT OF CANCER
1. FIELD
[0002] Provided herein are methods for treating, preventing or
managing
cancer, including specific leukemias by administering enantiomerically pure
(+)-1,4-
clihydro-74(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidiny1]-4-oxo-1-(2-
thiazoly1)-1,8-naphthyridine-3-carboxylic acid, which is also known as SNS-595
or
AG-7352. Also provided are doses, dosing regimens and dosages for SNS-595 and
its administration.
2. BACKGROUND
[0003] SNS-595 is chemically named (+)-1,4-dihydro-7-[(3S,4S)-3-
methoxy-4-(methylamino)-1-pyrrolidiny1]-4-oxo-1-(2-thiazoly1)-1,8-
naphthyridine-
3-carboxylic acid, and has the following structure:
0
002H
I I
HN6.0 N N
H3C1
L
H3C6 NS
[0004] SNS-595 is known for its anti-tumor activity. Trealiaent of the
following cancers with SNS-595 has been proposed in the literature: bladder
cancer,
breast cancer, cervical cancer, colon cancer, esophageal cancer, head and neck
cancer, liver cancer, lung cancer, melanoma, myeloma, neuroblastoma (Le., CNS
cancer), ovarian cancer, pancreatic cancer, prostate cancer, renal cancer,
sarcoma,
skin cancer, stomach cancer, testicular cancer, thyroid cancer and uterine
cancer.
Various dosing regimens have been reported, for example, see, U.S. Patent
Application Pub. Nos. 2005-0203120; 2005-0215583 and 2006-0025437.
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[0005] There continues to be a need for safe and effective dosages and
dosing regimens for administering SNS-595 in treating, preventing and managing
various cancers, including leukemias.
3. SUMMARY
[0006] SNS-595 is a known cytotoxic agent with utility against various
cancers. Herein are discussed novel treatment methods including the treatment
of
specific leukemias. In addition, described are unique dosing ranges, regimens
and
pharmaceutical doses.
[0007] The treatment, prevention or management of cancer using SNS-595,
pharmaceutical compositions thereof and unique dosing is described. Generally,
the
types of cancers that can be treated, prevented or managed using methods
provided
herein include, but are not limited to: bladder cancer, breast cancer,
cervical cancer,
colon cancer (including colorectal cancer), esophageal cancer, head and neck
cancer,
liver cancer, lung cancer (both small cell and non-small cell), melanoma,
myeloma,
neuroblastoma (i.e., CNS cancer), ovarian cancer, pancreatic cancer, prostate
cancer,
renal cancer, sarcoma (including osteosarcoma), skin cancer (including
squamous
cell carcinoma), stomach cancer, testicular cancer, thyroid cancer, and
uterine
cancer. The cancer can be relapsed, refractory or resistant to conventional
therapy.
[0008] In certain embodiments, the cancer includes hematologic
malignancies, including, but not limited to leukemias, lymphomas (Non-
Hodgkin's
Lymphoma), Hodgkin's disease (also called Hodgkin's Lymphoma) and myeloma.
The various forms of leukemias include, but are not limited to, chronic
lymphocytic
leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, acute
myelogenous leukemia and acute myeloblastic leukemia. The leukemia can be
relapsed, refractory or resistant. In certain embodiments, the hematologic
malignancy is promyelocytic leukemia, T-cell leukemia or lymphoblastic
leukemia.
[0009] Further provided are methods of treating, preventing or managing
cancer by administering SNS-595 in a certain manner. In certain embodiment,
the
methods comprise administering to a mammal a dose of about 1 mg/m2 to 150
mg/m2, about 1 mg/m2 to 100 mg/m2, 1 mg/m2 to 75 mg/m2, 15 mg/m2 to 80 mg/m2,
or about 3 mg/m2 to 24 mg/m2 of SNS-595, on the basis of body surface area. In
certain embodiment, the methods comprise administering to a mammal a dose of
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about 15g/m2, 25g/m2 or 50 mg/m2 of SNS-595, on the basis of body surface
area.
Additional dosing and dosing regimens are described in more detail herein
below.
[0010] Also provided herein are dosing and dosing regimens for solid
cancers. The administered dose of SNS-595 can be delivered as a single dose
such
as, for example, an IV push of 10-15 minutes duration (e.g., a single bolus
injection)
or over time such as, for example, a 24-hour period (e.g., continuous infusion
over
time or divided bolus doses over time) and is repeated as necessary, for
example,
until the patient experiences stable disease or regression, or until the
patient
experiences disease progression or unacceptable toxicity.
[0011] In some embodiments, SNS-595 can be cyclically administered to a
patient. Cycling therapy involves the administration of the 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.
[0012] In another embodiment, SNS-595 is administered in combination
with another drug ("second active agent") or another therapy conventionally
used to
treat, prevent or manage cancer, or the methods of dosing of SNS-595 described
herein can be applied in combination therapy settings. Second active agents
include
known small molecule, anticancer, antitumor or cytotoxic agents and large
molecules (e.g., proteins and antibodies), examples of which are provided
herein, as
well as stem cells or cord blood. Examples of such conventional therapies
include,
but are not limited to, surgery, chemotherapy, radiation therapy, hormonal
therapy,
biological therapy, immunotherapy, blood transfusions, and combinations
thereof.
[0013] Thus, in certain embodiment, provided herein are combinations for
treatment, prevention and management of solid tumors. In other embodiment,
provided herein are combinations for treatment, prevention and management of
leukemias and lymphomas.
[0014] Also provided are pharmaceutical compositions, single unit dosage
forms, and dosing regimens which comprise SNS-595, and a second, or
additional,
active agent. Second active agents include specific combinations, or
"cocktails," of
drugs or therapy, or both.
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4. BRIEF DESCRIPTION OF FIGURES
[0015] FIG. 1 depicts the plasma concentrations of SNS-595 over time
among the various patient cohorts dosed in the qwk x3 schedule.
[0016] FIG. 2 illustrates nuclear foci formation in HCT116 cells after
treatment with SNS-595, etoposide, bleomycin and cisplatin;
[0017] FIG. 3 depicts foci quantitation by measuring foci fluorescent
intensity;
[0018] FIG. 4 illustrates dependence of foci formation on dose and time;
[0019] FIG. 5 shows cells with more than 2 foci as a function of time and
SNS-595 concentration;
[0020] FIG. 6, illustrates DNA damage induced by SNS-595 and etoposide
in the presence and absence of caffeine, which is an inhibitor of ATM and ATR.
[0021] FIG. 7 shows DNA damage induced by SNS-595 and etoposide in the
presence (M059K cells) and absence (M059J cells) of DNA-PK;
[0022] FIGs. 8a-c demonstrate synergistic/additive effect of co-dosing SNS-
595 with various cytotoxic agents in HCT 116 colon carcinoma cells; and
[0023] FIG 8d demonstrates synergistic/additive effect of co-dosing SNS-
595 with various cytotoxic agents in H460 lung cancer cells;
[0024] FIG. 9 shows combination index when SNS-595 is dosed
simultaneously with a selection of DNA damaging agents and antimetabolites in
SKOV3 ovarian cancer cell line (+/+) and (-/-) for p53 expression, shown as
black
and grey diamonds, respectively; and
[0025] FIGs. 10 a-d demonstrate effect of co-dosing SNS-595 with various
cytotoxic agents in HCT 116 colon carcinoma cells.
[0026] FIG. 11 provides dose linearity of three weekly doses (qwk x3;
circles = week 1; triangles = week 2) and once every three week doses (q3wk;
diamonds) of SNS-595 in patients with advanced solid tumors.
[0027] FIG. 12 provides a comparison of anti-tumor activities of SNS-595,
etoposide, doxorubicin and irinotecan in CCRF-CEM xenograft model.
[0028] FIG. 13 provides a comparison of anti-tumor activities of SNS-595 (
at 20 mg/kg and 25 mg/kg), etoposide, doxorubicin and irinotecan in LM3-Jck
xenograft model.
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[0029] FIG. 14 shows cellularity in bone marrow 6 days post initial
injection
of SNS-595 in female CD-1 mice. SNS-595 was administered on day 0 and day 4.
All images shown at 10x magnification;
[0030] FIG. 15 provides neutrophil response to SNS-595 dose;
[0031] FIG. 16 provides neutrophil count at various SNS-595 doses by day
8;
[0032] FIG. 17 provides WBC count at various SNS-595 doses by day 8;
[0033] FIG. 18 provides platelet count at various SNS-595 doses by day 8;
[0034] FIG. 19 provides percent change in body weight at various time
intervals after administering SNS-595; and
[0035] FIG. 20 shows bone marrow rebound at day 12 after administering 20
mg/kg SNS-595.
5. 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 cited patents, applications, published applications and other
publications
are incorporated by reference in their entirety. In the event that 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-pynolidiny1]-4-oxo-1-(2-thiazoly1)-1,8-naphthyridine-
3-carboxylic acid is substantially free from (-)-1,4-dihydro-7-[(3S,4S)-3-
methoxy-4-
(methylamino)-1-pyrrolidiny1]-4-oxo-1-(2-thiazoly1)-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-pyrrolidiny1]-4-oxo-1-(2-thiazoly1)-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, 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-
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pyrrolidiny1]-4-oxo-1-(2-thiazoly1)-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-pyrrolidiny1]-4-oxo-1-(2-thiazoly1)-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-oxo-1-(2-thiazoly1)-1,8-naphthyridine-3-carboxylic acid, at
least
about 90% by weight (+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-
pyrrolidiny1]-4-oxo-1-(2-thiazoly1)-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-pyrrolidiny1]-4-oxo-1-(2-
thiazoly1)-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-pyrrolidiny1]-4-oxo-1-(2-thiazoly1)-1,8-naphthyridine-3-
carboxylic acid and at most about 3% by weight (-)-enantiomer.
[0039] 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.
[0040] The term "prevention" includes the inhibition of a symptom of the
particular disease or disorder. In some embodiments, patients with familial
history
of cancer are candidates for preventive regimens. Generally, the term
"preventing"
refers to administration of the drug prior to the onset of symptoms,
particularly to
patients at risk of cancer.
[0041] As used herein and unless otherwise indicated, the term "managing"
encompasses preventing the recurrence of the particular disease or disorder in
a
patient who had suffered from it, lengthening the time a patient who had
suffered
from the disease or disorder remains in remission, reducing mortality rates of
the
patients, and/or maintaining a reduction in severity or avoidance of a symptom
associated with the disease or condition being managed.
[0042] As used herein "subject" is an animal, typically a mammal, including
human, such as a patient.
[0043] As used herein, the term "cancer" includes, but is not limited to,
solid
tumors and blood born tumors. The term "cancer" refers to disease of skin
tissues,
organs, blood, and vessels, including, but not limited to, cancers of the
bladder, bone
or blood, brain, breast, cervix, chest, colon, endrometrium, esophagus, eye,
head,
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kidney, liver, lung, mouth, neck, ovaries, pancreas, prostate, rectum,
stomach, testis,
throat, and uterus.
[0044] As used herein, "hematologic malignancy" refers to cancer of the
body's.blood-forming and immune system-the bone marrow and lymphatic tissue.
Such cancers include leukemias, lymphomas (Non-Hodgkin's Lymphoma),
Hodgkin's disease (also called Hodgkin's Lymphoma) and myeloma.
[0045] The term "leukemia" refers to malignant neoplasms of the blood-
forming tissues. The leukemia includes, but is not limited to, chronic
lymphocytic
leukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia, acute
myelogenous leukemia and acute myeloblastic leukemia. The leukemia can be
relapsed, refractory or resistant to conventional therapy.
[0046] As used herein "promyelocytic leukemia" or "acute promyelocytic
leukemia" refers to a malignancy of the bone marrow in which there is a
deficiency
of mature blood cells in the myeloid line of cells and an excess of immature
cells
called promyelocytes. It is usually marked by an exchange of parts of
chromosomes
15 and 17.
[0047] As used herein "acute lymphocytic leukemia (ALL)", also known as
"acute lymphoblastic leukemia" refers to a malignant disease caused by the
abnormal growth and development of early nongranular white blood cell or
lymphocytes.
[0048] As used herein "T- cell leukemia" refers to a disease in which
certain
cells of the lymphoid system called T lymphocytes or T cells are malignant. T
cells
are white blood cells that normally can attack virus-infected cells, foreign
cells and
cancer cells and produce substances that regulate the immune response.
[0049] The term "relapsed" refers to a situation where patients who have
had
a remission of cancer after therapy have a return of cancer cells.
[0050] The term "refractory or resistant" refers to a circumstance where
patients, even after intensive treatment, have residual cancer cells in their
body.
[0051] As used herein, the IC50 refers to an amount, concentration or
dosage
of a particular test compound that achieves a 50% inhibition of a maximal
response
in an assay that measures such response.
[0052] As used herein, and unless otherwise specified, the terms
"therapeutically effective amount" and "effective amount" of a compound refer
to an
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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.
[0053] 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 compound can form a wide 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,
nap sylate, nitrate, panthothenate, phosphate/diphosphate, polygalacturonate,
salicylate, stearate, succinate, sulfate, tannate, tartrate, teoclate,
triethiodide and
pamoate. Under certain basic conditions, the compound 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.
[0054] 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-stoichiometeric amount of water bound by non-covalent
intermolecular forces.
[0055] 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).
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[0056] The terms "co-administration" and "in combination with" include the
administration of two therapeutic agents (for example, SNS-595 and another
anti-
cancer agent or second 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.
[0057] The term "the supportive care agent" refers to any substance that
treats, prevents or manages an adverse effect from SNS-595 treatment
6. DETAILED DESCRIPTION
6.1 SNS-595
[0058] The compound for use in the methods and compositions provided
herein is enantiomerically pure (+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-
(methylamino)-1-pyrrolidinyI1-4-oxo-1-(2-thiazoly1)-1,8-naphthyridine-3-
carboxylic
acid, which is also known as SNS-595 or AG-7352. SNS-595 has the following
chemical structure:
0
2JLC00H
) I
H3CHN....0 N N
S N
CHO
[0059] In certain embodiments, pharmaceutically acceptable salts, solvates,
hydrates or prodrugs of SNS-595 are used in the methods and compositions
provided herein.
[0060] 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.
Patent
No. 5,817,669, titled "Compounds, processes for the preparation thereof and
anti-
tumor agents," issued October 6, 1998, and in Japanese Patent Application No.
Hei
10-173986, to Chilcugi etal.
Certain exemplary pharmaceutical compositions comprising SNS-595
and methods of using the same are described in U.S. Patent Application Pub.
Nos.
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2005-0203120; 2005-0215583 and 2006-0025437.
6.2 METHODS OF USE
[0061] Proliferating cells undergo four phases of the cell cycle: GI, 5,
02,
and M. These phases were first identified by observing dividing cells as the
cells
progressed through DNA synthesis which became known as the synthesis or S
phase
of the cell cycle and mitosis and is known as the mitotic or M phase or S
phase of
the cell cycle. The observed gaps in time between the completion of DNA
synthesis
and mitosis and between mitosis to the next cycle of DNA synthesis are as the
GI
and 02 phases respectfully. Non-proliferating cells that retain the ability to
proliferate under the appropriate conditions are quiescent or in the Go state
and are
typically characterized as having exited the cell cycle.
[0062] SNS-595 is a cell cycle inhibitor and arrests cells at the 02
interface.
Without being limited by a particular theory, SNS-595 mediates the activation
of the
DNA-PK pathway which eventually leads to apoptotic cell death. These events
are
S-phase specific, i.e., they occur only during the S phase of the cell cycle.
Without
being limited by a particular theory, treatment with SNS-595 results in an
increase in
the number of double-strand DNA breaks that form during the S phase. This
damage impedes the ability of the cell to synthesize DNA and lengthens the
time the
cell spends in the S phase. Once DNA damage is detected in cells, markers for
apoptosis rapidly appear. This rapid onset of apoptosis appears to be p73
dependent
as shown by a more than 11 fold decrease in SNS-595 sensitivity in p73 null
cells as
compared to p73 containing cells.
[0063] As FIG. 7 exemplifies, the formation of double-strand breaks
activates, in a dose dependent manner, the DNA-PK mediated repair and
apoptotic
cellular machinery including but not limited to: i) DNA-PK expression; ii)
H2AX
phosphorylation; c-Abl phosphorylation; iv) p53 phosphorylation; v) p73
phosphorylation; vi) p21 expression; vii) caspase-9 activation; and Ali)
caspase-3
activation. When the DNA damage is sufficiently severe such that the double-
strand
breaks cannot be repaired through non-homologous end joining (NHED, the cell
rapidly enters apoptosis. Some cells are able to reach the 02 phase but are
subsequently arrested (mediated by cdc2/cyclin B) because the cells are too
damaged to enter into the M phase and also eventually becomes apoptotic.
Without
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being limited by a particular theory, because SNS-595 is S-phase selective,
doses of
SNS-595 that are cytotoxic to proliferating cells (thus are progressing
through the
cell cycle including the S phase) are non-lethal to non-proliferating cells.
6.2.1 Solid Tumors
[0064] Accordingly, provided herein are methods of treating, managing, or
preventing cancers comprising administering a dose of about 1 mg/m2 to about
100
mg/m2 of SNS-595 to a mammal in need of such treatment, management or
prevention. The cancer types include, but are not limited to, bladder cancer,
breast
cancer, cervical cancer, colon cancer (including colorectal cancer),
esophageal
cancer, head and neck cancer, liver cancer, lung cancer (both small cell and
non-
small cell), melanoma, myeloma, neuroblastoma, ovarian cancer, pancreatic
cancer,
prostate cancer, renal cancer, sarcoma (including osteosarcoma), skin cancer
(including squamous cell carcinoma), stomach cancer, testicular cancer,
thyroid
cancer, and uterine cancer. In one embodiment, the methods encompass treating,
preventing or managing colon, pancreas, breast, mesothelioma,
cholangiocarcinoma,
leiomyosarcoma, liposarcoma, melanoma, nasopharyngeal, neuroendocrine,
ovarian,
renal, salivary gland, small cell lung cancer, or spindle cell carcinoma.
6.2.2 Leukemias
[0065] In one embodiment, methods provided herein encompass treating,
preventing or managing various types of leukemias such as chronic lymphocytic
leukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia, acute
myelogenous leukemia, and acute myeloblastic leukemia.
[0066] In some embodiments, the methods encompass treating, preventing or
managing acute leukemia, such as AML, which includes, but is not limited to
undifferentiated AML (MO), myeloblastic leukemia (M1), myeloblastic leukemia
(M2), promyelocytic leukemia (M3 or M3 variant [M3V]), myelomonocytic
leukemia (M4 or M4 variant with eosinophilia [M4E]), monocytic leukemia (M5),
erythroleukemia (M6), megakaryoblastic leukemia (M7). In some embodiments,
acute lymphocytic leukemia (ALL) includes leukemia that originates in the
blast
cells of the bone marrow (B-cells), thymus (T-cells), and lymph nodes. The
acute
lymphocytic leukemia is categorized according to the French-American-British
(FAB) Morphological Classification Scheme as Li - Mature-appearing
lymphoblasts
(T-cells or pre-B-cells), L2 - Immature and pleomorphic (variously shaped)
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lymphoblasts (T-cells or pre-B-cells), and L3 - Lymphoblasts (B-cells;
Burkitt's
cells).
[0067] In one embodiment, the acute myelogenous leukemia is
undifferentiated AML (MO).
[0068] In one embodiment, the acute myelogenous leukemia is myeloblastic
leukemia (M1).
[0069] In one embodiment, the acute myelogenous leukemia is myeloblastic
leukemia (M2).
[0070] In one embodiment, the acute myelogenous leukemia is
promyelocytic leukemia (M3 or M3 variant [M3V]).
[0071] In one embodiment, the acute myelogenous leukemia is
myelomonocytic leukemia (M4 or M4 variant with eosinophilia [M4E]).
[0072] In one embodiment, the acute myelogenous leukemia is monocytic
leukemia (M5).
[0073] In one embodiment, the acute myelogenous leukemia is
erythroleukemia (M6).
[0074] In one embodiment, the acute myelogenous leukemia is
megakaryoblastic leukemia (M7).
[0075] In one embodiment, the acute lymphocytic leukemia originates in the
blast cells of the bone marrow (B-cells)
[0076] In one embodiment, the acute lymphocytic leukemia originates in the
thymus (T-cells).
[0077] In one embodiment, the acute lymphocytic leukemia originates in the
lymph nodes.
[0078] In one embodiment, the acute lymphocytic leukemia is Li type
characterized by mature-appearing lymphoblasts (T-cells or pre-B-cells).
[0079] In one embodiment, the acute lymphocytic leukemia is L2 type
characterized by immature and pleomorphic (variously shaped) lymphoblasts (T-
cells or pre-B-cells).
[0080] In one embodiment, the acute lymphocytic leukemia is L3 type
characterized by lymphoblasts (B-cells; Burkitt's cells).
[0081] In certain embodiments, the acute myelogenous leukemia is
promyelocytic leukemia, or lymphoblastic leukemia. In certain embodiments, the
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acute lymphocytic leukemia is T-cell leukemia. In one embodiment, methods
provided herein encompass methods of treating, preventing or managing
promyelocytic leukemia, T-cell leukemia or lymphoblastic leukemia. In one
embodiment, the T-cell leukemia is peripheral T-cell leukemia, T-cell
lymphoblastic
leukemia, cutaneous T-cell leukemia, and adult T-cell leukemia.
[0082] In some embodiments, SNS-595 is used to treat drug resistant
leukemias, such as chronic myelogenous leukemia (CML). Thus, treatment with
SNS-595 could provide an alternative for patients who do not respond to other
methods of treatment. In some embodiments, such other methods of treatment
encompass treatment with Gleevac . In some embodiments, provided herein are
methods of treatment of Philadelphia chromosome positive chronic myelogenous
leukemia (Ph+CML). In some embodiments, provided herein are methods of
treatment of Gleevac resistant Philadelphia chromosome positive chronic
myelogenous leukemia (Ph+CML).
[0083] The methods provided herein encompass treating patients who have
been previously treated for cancer, but are non-responsive to standard
therapies, as
well as those who have not previously been treated. Also encompassed are
methods
of treating patients regardless of patient's age, although some diseases or
disorders
are more common in certain age groups. Further provided are methods of
treating
patients who have undergone surgery in an attempt to treat the disease or
condition
at issue, as well as those who have not. Because patients with cancer have
heterogenous 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 therapy that
can be
effectively used to treat an individual patient with cancer.
[0084] The administered dose of SNS-595 can be delivered as a single dose
such as, for example, an IV push of 10-15 minutes duration (e.g. a single
bolus
injection) or over time such as, for example, a 24-hour period (e.g.,
continuous
infusion over time or divided bolus doses over time) and is repeated as
necessary,
for example, until the patient experiences stable disease or regression, or
until the
patient experiences disease progression or unacceptable toxicity. For example,
stable disease for solid tumors generally means that the perpendicular
diameter of
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measurable lesions has not increased by 25% or more from the last measurement.
See e.g., Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines,
Journal of the National Cancer Institute 92(3): 205-216 (2000). Stable disease
or
lack thereof is determined by methods known in the art such as evaluation of
patient .
symptoms, physical examination, visualization of the tumor that has been
imaged
using X-ray, CAT, PET, or MRI scan and other commonly accepted evaluation
modalities.
[0085] In another embodiment, the dose is about 10 mg/ m2-100 mg/ m2. In
another embodiment, the dose is about 30 mg/ m2- 75 mg/ m2. In another
embodiment, the dose is about 40 mg/ m2- 80 mg/ m2. In another embodiment, the
dose is about 50 mg/ m2- 90 mg/ m2. In another embodiment, the dose is about
15
mg/ m2- 80 mg/ m2.
[0086] In another embodiment the dose is about 20 mg/ m2-30 mg/m2. In
another embodiment the dose is about 25 mg/m2-35 mg/m2. In another embodiment
the dose is about 40 mg/m2-50 mg/m2. In another embodiment the dose is about
45
mg/m2-55 mg/m2. In another embodiment the dose is about 50 mg/m2-60 mg/m2. In
another embodiment the dose is about 55 mg/m2-65 mg/m2. In another embodiment
the dose is about 60 mg/m2-70 mg/ m2. In another embodiment the dose is about
65
mg/m2-75 mg/m2. In another embodiment the dose is about 70 mg/m2-80 mg/m2. In
another embodiment the dose is about 75 mg/m2-85 mg/m2. In another embodiment
the dose is about 80 mg/m2-90 mg/m2. In another embodiment the dose is about
85
mg/m2-95 mg/m2. In another embodiment the dose is about 90 mg/m2-100 mg/m2.
[0087] In other embodiments, SNS-595 is administered in combination with
another drug ("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 an SNS-595 include, but are not limited
to,
surgery, immunotherapy, biological therapy, radiation therapy and other non-
drug
based therapies presently used to treat, prevent or manage cancer. Various
dosing
regimens for administration of SNS-595 alone and/or in combination therapy are
discussed herein.
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[0088] Also provided are pharmaceutical compositions (e.g., single unit
dosage forms) that can be used in methods disclosed herein. Particular
pharmaceutical compositions comprise SNS-595 and a second active agent.
6.3 DOSES AND DOSING REGIMENS
[0089] In one embodiment, the methods of treating, preventing or managing
cancers provided herein comprise administering to a patient on the basis of
body
surface area, a dose of about 1 mg/m2 to 150 mg/m2 of SNS-595. In another
embodiment, the methods of comprise administering a dose of about 1 mg/m2 to
100
mg/m2 of SNS-595. In another embodiment, the methods of comprise administering
a dose of about 1 mg/m2 to 75 mg/m2 of SNS-595. In another embodiment, the
methods of comprise administering a dose of about 1 mg/m2 to 60 mg/m2 of SNS-
595. In another embodiment, the methods of comprise administering a dose of
about
1 mg/m2 to 50 mg/m2 of SNS-595. In another embodiment, the methods of
comprise administering a dose of about 1 mg/m2 to 48 mg/m2 of SNS-595. In
another embodiment, the methods of comprise administering a dose of about 1
mg/m2 to 24 mg/m2 of SNS-595. In another embodiment, the methods of comprise
administering a dose of about 3 mg/m2 to 27 mg/m2 of SNS-595 on the basis of
body
surface area. In another embodiment, the methods of comprise administering a
dose
of about 3 mg/m2 to 24 mg/m2 of SNS-595 on the basis of body surface area. In
another embodiment, the methods of comprise administering a dose of about 10
mg/m2 to 90 mg/m2 of SNS-595 on the basis of body surface area. In another
embodiment, the methods of comprise administering a dose of about 15 mg/m2 to
80
mg/m2 of SNS-595 on the basis of body surface area. Body surface area
calculations
can be calculated for example, with the Mosteller formula wherein:
BSA(m2)=square root of [(height(cm) x weight(kg)/3600].
[0090] In another embodiment, the dose is 3 mg/ m2 to 24 mg/m2 on the
basis of body surface area. In another embodiment, the dose is 3 mg/m2 to 18
mg/m2 on the basis of body surface area. In another embodiment, the dose is 3
mg/m2 to 15 mg/m2. In another embodiment, the dose is 1 mg/m2, 2 mg/m2, 3
mg/m2, 4 mg/m2, 5 mg/m2, 6 mg/m2, 7 mg/m2, 8 mg/m2, 9 mg/m2, 10 mg/m2, 11
mg/m2, 12 mg/m2, 13 mg/m2, 14 mg/m2, 15 mg/m2, 16 mg/m2, 17 mg/m2, 18 mg/m2,
19 mg/m2, 20 mg/m2, 21 mg/m2, 22 mg/m2, 23 mg/m2, 24 mg/m2, 25 mg/m2, 26
mg/m2, 27 mg/m2, 30 mg/m2, 36 mg/m2, 42 mg/m2, 48 mg/m2, 50 mg/m2, 55 mg/m2,
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60 mg/m2 or 65 mg/m2 on the basis of body surface area. In another embodiment,
the dose is 3 mg/m2, 6 mg/m2, 9 mg/m2, 12 mg/m2, 15 mg/m2, 18 mg/m2, 21 mg/m2
24 mg/m2 , 25 mg/m2, 27 mg/m2, 36 mg/m2, 48 mg/m2 or 50 mg/m2.
[0091] In one embodiment, the dose is 15 mg/m2 on the basis of body
surface area. In another embodiment, the dose is 25 mg/m2 on the basis of body
surface area. In another embodiment, the dose is 30 mg/m2 on the basis of body
surface area. In one embodiment, the dose is 50 mg/m2 on the basis of body
surface
area.
[0092] In another embodiment, the dose is 15 mg/ m2 to 80 mg/m2 on the
basis of body surface area. In another embodiment, the dose is 15 mg/m2 to 75
mg/m2 on the basis of body surface area. In another embodiment, the dose is 20
mg/m2 to 65 mg/m2. In another embodiment, the dose is 30 mg/m2 to 50 mg/m2. In
another embodiment, the dose is 15 mg/m2, 20 mg/m2, 25 mg/m2, 30 mg/m2, 35
mg/m2, 40 mg/m2, 45 mg/m2, 50 mg/m2, 55 mg/m2, 60 mg/m2, 65 mg/m2, 70 mg/m2,
75 mg/m2, or 80 mg/m2 on the basis of body surface area.
[0093] The administered dose of SNS-595 can be expressed in units other
than as mg/m2. 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/m2 to mg/kg
to
given either the height or weight of a subject or both (see,
http:///www.fda.gov/cder/cancer/animalframe.htm). For example, a dose of 1
mg/m2
to 30 mg/m2 for a 65 kg human is approximately equal to 0.026 mg/kg to 0.79
mg/kg. In another example, a dose of 3 mg/m2 for a 65 kg human is
approximately
equal to 0.078 mg/kg. In another example, a dose of 15 mg/m2 to 80 mg/m2 for a
65
kg human is approximately equal to 0.39 mg/kg to 2.11 mg/kg.
[0094] In certain embodiments, the administered dose of SNS-595 can be
delivered as a single dose such as, for example, an IV push of 10-15 minutes
duration (e.g. a single bolus IV injection) or over time such as, for example,
a 24-
hour period (e.g., continuous infusion over time or divided bolus doses over
time)
and is repeated as necessary, for example, 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.
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[0095] The amount of the pharmaceutical composition administered
according to the methods provided herein will depend on the mammal being
treated,
the severity of the disorder or symptom of the disorder, the manner of
administration, the frequency of administration and the judgment of the
prescribing
physician.
[0096] In some embodiments, the frequency of administration is in the range
of about a daily dose to about a monthly dose. In certain embodiments,
administration is once a day, once every other day, twice a week, once every
week,
once every two weeks, once every three weeks, or once every four weeks. In one
embodiment, the pharmaceutical composition provided herein is administered
weekly.
[0097] 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.
[0098] Consequently, in one embodiment, SNS-595 is administered weekly
in a single or divided doses in a three to six week cycle with a rest period
of about 1
to about 30 days. In another embodiment, SNS-595 is administered weekly in a
single or divided doses for one week, two weeks, three weeks, four weeks, five
weeks or six weeks with a rest period of 1, 3, 5, 7, 9, 12, 14, 16, 18, 20,
22, 24, 26,
28, 29 or 30 days. In some embodiments, the waiting period is 14 days. In some
embodiments, the waiting period is 28 days. In one embodiment, the waiting
period
is until there is sufficient bone Marrow recovery. The frequency, number and
length
of dosing cycles can be increased or decreased. Thus, another embodiment
encompasses the administration of SNS-595 for more cycles than are typical
when
it is administered alone.
[0099] In one embodiment, the methods provided herein comprise: i)
administering a dose of about 1 mg/m2 to 150 mg/m2 of SNS-595 to a patient;
ii)
waiting a period of at least one day where the mammal is not administered any
SNS-
595; and iii) administering another dose of about 1 mg/m2 to 150 mg/m2 of SNS-
595
to the patient. In one embodiment, steps ii)-iii) are repeated a plurality of
times. In
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another embodiment, the method comprises administering a dose of 1 mg/m2-100
mg/m2 in steps i) and iii).
[00100] In one embodiment, for example, in methods for treatment of
certain
leukemias, the methods provided herein comprise: i) administering a dose of
about
mg/m2-150 mg/m2 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 mg/m2-150 mg/m2 of SNS-595 to the mammal; and, iv) repeating
steps ii)-iii) a plurality of times. In another embodiment, the method
comprises
administering a dose of 10 mg/m2-100 mg/m2 in steps i) and iii).
[00101] In one embodiment, the methods provided herein comprise: i)
administering a dose of about 1 mg/m2 to 75 mg/m2 of SNS-595 to a patient; ii)
waiting a period of at least one day where the mammal is not administered any
SNS-
595; and iii) administering another dose of about 1 mg/m2 to 75 mg/m2 of SNS-
595
to the patient. In one embodiment, steps ii)-iii) are repeated a plurality of
times.
[00102] In one embodiment, the methods provided herein comprise: i)
administering a dose of about 1 mg/m2 to 48 mg/m2 of SNS-595 to a patient; ii)
waiting a period of at least one day where the mammal is not administered any
SNS-
595; and iii) administering another dose of about 1 mg/m2 to 48 mg/m2 of SNS-
595
to the patient. In one embodiment, steps ii)-iii) are repeated a plurality of
times.
[00103] In one embodiment, the methods provided herein comprise: i)
administering a dose of about 1 mg/m2 to 24 mg/m2 of SNS-595 to a patient; ii)
waiting a period of at least one day where the mammal is not administered any
SNS-
595; and iii) administering another dose of about 1 mg/m2 to 24 mg/m2 of SNS-
595
to the patient. In one embodiment, steps ii)-iii) are repeated a plurality of
times.
[00104] In another embodiment, the method comprises administering a
dose
of about 3 mg/m2 to 24 mg/m2 in steps i) and iii). In yet another embodiment,
the
method comprises administering a dose of about 15 mg/m2 in steps i) and iii).
In yet
another embodiment, the method comprises administering a dose of about 1 mg/m2
to 40 mg/m2, about 1.5 mg/m2 to 30 mg/m2, about 2 mg/m2 to 25 mg/m2 or about 3
mg/m2 to 24 mg/m2 in steps i) and iii).
[00105] In another embodiment, the method comprises administering a
dose
of about 15 mg/m2 to 80 mg/m2 in steps i) and iii). In yet another embodiment,
the
method comprises administering a dose of about 15 mg/m2 to 75 mg/m2 in steps
i)
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and iii). In yet another embodiment, the method comprises administering a dose
of
about 20 mg/m2 to 65 mg/m2, about 30 mg/m2 to 50 mg/m2, about 35 mg/m2, about
40 mg/m2, or about 45 mg/m2 in steps i) and iii).
[00106] In the above methods, for example, if the waiting period
were 6 days,
then the initial dose of SNS-595 is administered on Day 1 (step i); the
waiting period
is six days (step ii); and the following dose of SNS-595 is administered on
Day 8
(step iii). Other exemplary time periods include 2 days, 3 days, 5 days, 7
days, 10
days, 12 days, 13 days, 14 days, 15 days, 17 days, 20 days, 27 days and 28
days. In
another embodiment, the waiting period is at least 2 days and steps ii)
through iii)
are repeated at least three times. In another embodiment, the waiting period
is at
least 3 days and steps ii) through iii) are repeated at least five times. In
another
embodiment, the waiting period is at least 3 days and steps ii) through iii)
are
repeated at least three times. In another embodiment, the waiting period is at
least 3
days and steps ii) through iii) are repeated at least five times. In another
embodiment, the waiting period is at least 6 days and steps ii) through iii)
are
repeated at least three times. In another embodiment, the waiting period is at
least 6
days and steps ii) through iii) are repeated at least five times. In another
embodiment, the waiting period is at least 14 days and steps ii) through iii)
are
repeated at least three times. In another embodiment, the waiting period is at
least
20 days and steps ii) through iii) are repeated at least three times. In
another
embodiment, the waiting period is at least 20 days and steps ii) through iii)
are
repeated at least five times. In another embodiment, the waiting period is at
least 28
days and steps ii) through iii) are repeated at least three times. In another
embodiment, the waiting period is at least 27 days and steps ii) through iii)
are
repeated at least five times. In another embodiment, the waiting period is at
least 28
days and steps ii) through iii) are repeated at least five times.
[00107] In another embodiment, the dosing method comprises
administering a
dose of SNS-595 twice a week (dosing on days 1, 4, 8 and 11) to a mammal. In
another embodiment, the dosing method comprises administering a weekly dose of
SNS-595 to a mammal. In another embodiment, the dosing method comprises
administering a dose of SNS-595 to a mammal every two weeks. In another
embodiment, the dosing method comprises administering a dose of SNS-595 to a
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mammal every three weeks. In another embodiment, the dosing method comprises
administering a dose of SNS-595 to a mammal every four weeks.
[00108] In another embodiment, the dosing method comprises a cycle
wherein the cycle comprises administering a dose of SNS-595 to a mammal once a
week for three weeks followed by a period of at least 14 days where no SNS-595
is
administered to the mammal and wherein the cycle is repeated a plurality of
times.
In another embodiment, the period where no SNS-595 is administered is 14 days.
In
another embodiment, the period where no SNS-595 is administered is 21 days.
[00109] In another embodiment, the methods provided herein comprise:
i)
administering a dose of about 1 mg/m2 to 100 mg/m2 of SNS-595 to a mammal once
a week for 3 weeks; ii) waiting a period of 14 days where the mammal is not
administered any SNS-595; and iii) administering another dose of about 1 mg/m2
to
100 mg/m2 of SNS-595 to the mammal once a week for 3 weeks. In one
embodiment, steps ii)-iii) are repeated a plurality of times.
[00110] In another embodiment, the methods provided herein comprise:
i)
administering a dose of about 1 mg/m2 to 75 mg/m2 of SNS-595 to a mammal once
a
week for 3 weeks; ii) waiting a period of 14 days where the mammal is not
administered any SNS-595; and iii) administering another dose of about 1 mg/m2
to
75 mg/m2 of SNS-595 to the mammal once a week for 3 weeks. In one
embodiment, steps ii)-iii) are repeated a plurality of times.
[00111] In another embodiment, the methods provided herein comprise:
i)
administering a dose of about 1 mg/m2 to 60 mg/m2 of SNS-595 to a mammal once
a
week for 3 weeks; ii) waiting a period of 14 days where the mammal is not
administered any SNS-595; and iii) administering another dose of about 1 mg/m2
to
60 mg/m2 of SNS-595 to the mammal once a week for 3 weeks. In one
embodiment, steps ii)-iii) are repeated a plurality of times.
[00112] In another embodiment, the methods provided herein comprise:
i)
administering a dose of about 1 mg/m2-50 mg/m2 of SNS-595 to a mammal once a
week for 3 weeks; ii) waiting a period of 14 days where the mammal is not
administered any SNS-595; iii) administering another dose of about 1 mg/m2-50
mg/m2 of SNS-595 to the mammal once a week for 3 weeks; and, iv) repeating
steps
ii)-iii) a plurality of times.
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[00113] In another embodiment, the methods provided herein
comprise: i)
administering a dose of about 1 mg/m2 to 48 mg/m2 of SNS-595 to a mammal once
a
week for 3 weeks; ii) waiting a period of 14 days where the mammal is not
administered any SNS-595; and iii) administering another dose of about 1 mg/m2
to
48 mg/m2 of SNS-595 to the mammal once a week for 3 weeks. In one
embodiment, steps ii)-iii) are repeated a plurality of times.
[00114] In another embodiment, the methods provided herein
comprise: i)
administering a dose of about 1 mg/m2 to 24 mg/m2 of SNS-595 to a mammal once
a
week for 3 weeks; ii) waiting a period of 14 days where the mammal is not
administered any SNS-595; and iii) administering another dose of about 1 mg/m2
to
24 mg/m2 of SNS-595 to the mammal once a week for 3 weeks. In one
embodiment, steps ii)-iii) are repeated a plurality of times.
[00115] In another embodiment, the methods provided herein
comprise: i)
administering a dose of about 2 mg/m2 to 40 mg/m2 of SNS-595 to a mammal once
a
week for 3 weeks; ii) waiting a period of 14 days where the mammal is not
administered any SNS-595; and iii) administering another dose of 2 mg/m2 to 40
mg/m2 of SNS-595 to the mammal once a week for 3 weeks. In one embodiment,
steps ii)-iii) are repeated a plurality of times.
[00116] In another embodiment, the methods provided herein
comprise: i)
administering a dose of about 3 mg/m2 to 24 mg/m2 of SNS-595 to a mammal once
a
week for 3 weeks; ii) waiting a period of 14 days where the mammal is not
administered any SNS-595; and iii) administering another dose of about 3 mg/m2
to
24 mg/m2 of SNS-595 to the mammal once a week for 3 weeks. In one
embodiment, steps ii)-iii) are repeated a plurality of times.
[00117] In another embodiment, the methods provided herein
comprise: i)
administering a dose of about 3 mg/m2 to 24 mg/m2 of SNS-595 to a mammal once
a
week for 3 weeks (e.g. dosing in days 1, 8 and 15); ii) waiting a period of at
least 28
days where the mammal is not administered any SNS-595; and iii) administering
another dose of about 3 mg/m2 to 24 mg/m2 of SNS-595 to the mammal once a week
for 3 weeks. In one embodiment, steps ii)-iii) are repeated a plurality of
times.
[00118] In another embodiment, the methods provided herein
comprise: i)
administering a dose of about 3 mg/m2 to 24 mg/m2 of SNS-595 to a mammal twice
a week for 2 weeks (dosing in days 1, 4, 8 and 11); ii) waiting a period of at
least 28
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days where the mammal is not administered any SNS-595; and iii) administering
another dose of about 3 mg/m2 to 24 mg/m2 of SNS-595 to the mammal twice a
week for 2 weeks (dosing in days 1, 4, 8 and 11). In one embodiment, steps ii)-
iii)
are repeated a plurality of times.
[00119] In another embodiment, the methods provided herein comprise:
i)
administering a dose of about 3 mg/m2 to 24 mg/m2 of SNS-595 to a mammal once
a
week for 3 weeks (e.g. dosing in days 1, 8 and 15); ii) waiting a period of 28
days
where the mammal is not administered any SNS-595; and iii) administering
another
dose of about 3 mg/m2 to 24 mg/m2 of SNS-595 to the mammal once a week for 3
weeks. In one embodiment, steps ii)-iii) are repeated a plurality of times.
[00120] In another embodiment, the methods provided herein comprise:
i)
administering a dose of about 3 mg/m2 to 24 mg/m2 of SNS-595 to a mammal twice
a week for 2 weeks (dosing in days 1, 4, 8 and 11); ii) waiting a period of 28
days
where the mammal is not administered any SNS-595; and iii) administering
another
dose of about 3 mg/m2 to 24 mg/m2 of SNS-595 to the mammal twice a week for 2
weeks (dosing in days 1, 4, 8 and 11). In one embodiment, steps ii)-iii) are
repeated
a plurality of times.
[00121] In another embodiment, the methods provided herein comprise:
i)
administering a dose of about 15 mg/m2 to 80 mg/m2 of SNS-595 to a mammal once
a week for 3 weeks; ii) waiting a period of 14 days where the mammal is not
administered any SNS-595; and iii) administering another dose of about 15
mg/m2 to
80 mg/m2 of SNS-595 to the mammal once a week for 3 weeks. In one
embodiment, steps ii)-iii) are repeated a plurality of times.
[00122] In another embodiment, the methods provided herein comprise:
i)
administering a dose of about 15 mg/m2 to 80 mg/m2 of SNS-595 to a mammal once
a week for 3 weeks (e.g. dosing in days 1, 8 and 15); ii) waiting a period of
at least
28 days where the mammal is not administered any SNS-595; and iii)
administering
another dose of about 15 mg/m2 to 80 mg/m2 of SNS-595 to the mammal once a
week for 3 weeks. In one embodiment, steps ii)-iii) are repeated a plurality
of times.
[00123] In another embodiment, the methods provided herein comprise:
i)
administering a dose of about 15 mg/m2 to 80 mg/m2 of SNS-595 to a mammal
twice a week for 2 weeks (dosing in days 1, 4, 8 and 11); ii) waiting a period
of at
least 28 days where the mammal is not administered any SNS-595; and iii)
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administering another dose of about 15 mg/m2 to 80 mg/m2 of SNS-595 to the
mammal twice a week for 2 weeks (dosing in days 1, 4, 8 and 11). In one
embodiment, steps ii)-iii) are repeated a plurality of times.
[00124] In another embodiment, the methods provided herein comprise:
i)
administering a dose of about 15 mg/m2 to 80 mg/m2 of SNS-595 to a mammal once
a week for 3 weeks (e.g. dosing in days 1, 8 and 15); ii) waiting a period of
28 days
where the mammal is not administered any SNS-595; and iii) administering
another
dose of about 15 mg/m2 to 80 mg/m2 of SNS-595 to the mammal once a week for 3
weeks. In one embodiment, steps ii)-iii) are repeated a plurality of times.
[00125] In another embodiment, the methods provided herein comprise:
i)
administering a dose of about 15 mg/m2 to 80 mg/m2 of SNS-595 to a mammal
twice a week for 2 weeks (dosing in days 1, 4, 8 and 11); ii) waiting a period
of 28
days where the mammal is not administered any SNS-595; and iii) administering
another dose of about 15 mg/m2 to 80 mg/m2 of SNS-595 to the mammal twice a
week for 2 weeks (dosing in days 1, 4, 8 and 11). In one embodiment, steps ii)-
iii)
are repeated a plurality of times.
[00126] In another embodiment, the method comprises administering a
dose
of 1 mg/m2 to 100 mg/m2 of SNS-595 to a patient once a week wherein the one-
week period comprises a treatment cycle and the treatment cycle is repeated at
least
three times. In another embodiment, the method comprises administering a dose
of
1 mg/m2 to 75 mg/m2 of SNS-595 to a patient once a week wherein the one-week
period comprises a treatment cycle and the treatment cycle is repeated at
least three
times. In another embodiment, the method comprises administering a dose of 1
mg/m2 to 60 mg/m2 of SNS-595 to a patient once a week wherein the one-week
period comprises a treatment cycle and the treatment cycle is repeated at
least three
times. In another embodiment, the method comprises administering a dose of 1
mg/m2 to 48 mg/m2 of SNS-595 to a patient once a week wherein the one-week
period comprises a treatment cycle and the treatment cycle is repeated at
least three
times. In another embodiment, the method comprises administering a dose of 1
mg/m2 to 24 mg/m2 of SNS-595 to a patient once a week wherein the one-week
period comprises a treatment cycle and the treatment cycle is repeated at
least three
times. In another embodiment, the dose is about 2 mg/m2 to 40 mg/m2 once a
week
wherein the one-week period comprises a treatment cycle and the treatment
cycle is
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repeated at least three times. In another embodiment, the dose is about 3
mg/m2 to
24 mg/m2 once a week wherein the one-week period comprises a treatment cycle
and the treatment cycle is repeated at least three times. In another
embodiment, the
dose is about 15 mg/m2 once a week wherein the one-week period comprises a
treatment cycle and the treatment cycle is repeated at least three times.
[00127] In another embodiment, the method comprises administering a
dose
of 15 mg/m2 to 80 mg/m2 of SNS-595 to a patient once a week wherein the one-
week period comprises a treatment cycle and the treatment cycle is repeated at
least
throe times. In another embodiment, the method comprises administering a dose
of
15 mg/m2 to 75 mg/m2 of SNS-595 to a patient once a week wherein the one-week
period comprises a treatment cycle and the treatment cycle is repeated at
least three
times. In another embodiment, the method comprises administering a dose of 20
mg/m2 to 65 mg/m2 of SNS-595 to a patient once a week wherein the one-week
period comprises a treatment cycle and the treatment cycle is repeated at
least three
times. In another embodiment, the method comprises administering a dose of 30
mg/m2 to 50 mg/m2 of SNS-595 to a patient once a week wherein the one-week
period comprises a treatment cycle and the treatment cycle is repeated at
least three
times.
[00128] In some embodiments, the method comprises administering a
dose of
about 1 mg/m2 to 40 mg/m2 of SNS-595 to a patient once a week (e.g. dosing in
days 1, 8 and 15) wherein the one-week period comprises a treatment cycle and
the
treatment cycle is repeated at least three times followed by a waiting period
of at
least 28 days. In some embodiments, the method comprises administering a dose
of
about 1 mg/m2 to 40 mg/m2 of SNS-595 to a patient twice a week (dosing in days
1,
4, 8, and 11) wherein the one-week period comprises a treatment cycle and the
treatment cycle is repeated at least three times followed by a waiting period
of at
least 28 days. In some embodiments, the method comprises administering a dose
of
about 1 mg/m2 to 40 mg/m2 of SNS-595 to a patient once a week (e.g. dosing in
days 1, 8 and 15) wherein the one-week period comprises a treatment cycle and
the
treatment cycle is repeated at least three times followed by a waiting period
of 28
days. In some embodiments, the method comprises administering a dose of about
1
mg/m2 to 40 mg/m2 of SNS-595 to a patient twice a week (dosing in days 1, 4,
8,
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and 11) wherein the one-week period comprises a treatment cycle and the
treatment
cycle is repeated at least three times followed by a waiting period of 28
days.
[00129] In some embodiments, the method comprises administering a
dose of
about 3 mg/m2 to 24 mg/m2 of SNS-595 to a patient once a week (e.g. dosing in
days 1, 8 and 15) wherein the one-week period comprises a treatment cycle and
the
treatment cycle is repeated at least three times followed by a waiting period
of at
least 28 days. In some embodiments, the method comprises administering a dose
of
about 3 mg/m2 to 24 mg/m2 of SNS-595 to a patient twice a week (dosing in days
1,
4, 8, and 11) wherein the one-week period comprises a treatment cycle and the
treatment cycle is repeated at least three times followed by a waiting period
of at
least 28 days. In some embodiments, the method comprises administering a dose
of
about 3 mg/m2 to 24 mg/m2 of SNS-595 to a patient once a week (e.g dosing in
days 1, 8 and 15) wherein the one-week period comprises a treatment cycle and
the
treatment cycle is repeated at least three times followed by a waiting period
of 28
days. In some embodiments, the method comprises administering a dose of about
3
mg/m2 to 24 mg/m2 of SNS-595 to a patient twice a week (dosing in days 1, 4,
8,
and 11) wherein the one-week period comprises a treatment cycle and the
treatment
cycle is repeated at least three times followed by a waiting period of 28
days.
[00130] In some embodiments, the method comprises administering a
dose of
about 15 mg/m2 to 80 mg/m2 of SNS-595 to a patient once a week (e.g. dosing in
days 1, 8 and 15) wherein the one-week period comprises a treatment cycle and
the
treatment cycle is repeated at least three times followed by a waiting period
of at
least 28 days. In some embodiments, the method comprises administering a dose
of
about 15 mg/m2 to 80 mg/m2 of SNS-595 to a patient twice a week (dosing in
days
1, 4, 8, and 11) wherein the one-week period comprises a treatment cycle and
the
treatment cycle is repeated at least three times followed by a waiting period
of at
least 28 days. In some embodiments, the method comprises administering a dose
of
about 15 mg/m2 to 80 mg/m2 of SNS-595 to a patient once a week (e.g. dosing in
days 1, 8 and 15) wherein the one-week period comprises a treatment cycle and
the
treatment cycle is repeated at least three times followed by a waiting period
of 28
days. In some embodiments, the method comprises administering a dose of about
15 mg/m2 to 80 mg/m2 of SNS-595 to a patient twice a week (dosing in days 1,
4, 8,
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and 11) wherein the one-week period comprises a treatment cycle and the
treatment
cycle is repeated at least three times followed by a waiting period of 28
days.
[00131] In another embodiment, the method comprises administering a
dose
of about 1 mg/m2-50 mg/m2 of SNS-595 to a mammal once a week wherein the one-
week period comprises a treatment cycle and the treatment cycle is repeated at
least
twice. In another embodiment, the dose is about 2 mg/m2-40 mg/m2. In another
embodiment, the dose is about 3 mg/m2-24 mg/m2. In another embodiment, the
dose
is about 4 mg/m2-20 mg/m2.
6.4 EXEMPLARY DOSING REGIMENS
[00132] Exemplary dosing regimens in connection with specific
cancers are
provide below. These dosing regimens are intended to be illustrative, but not
exclusive.
[00133] In one aspect a method of treating a solid tumor is
provided. The
method comprises:
i) administering a dose of about 1 mg/m2 to 100 mg/m2 of SNS-
595 to a patient;
ii) waiting a period of at least six days where the subject is not
administered any SNS-595;
iii) administering another dose of about 1 mg/m2 to 100 mg/m2 of
SNS-595 to the patient; and,
iv) repeating steps ii)-iii) a plurality of times.
[00134] In another aspect, a method of treating solid tumors
comprises
administering a dose of about 1 mg/m2 to 75 mg/m2 of SNS-595 to a patient once
a
week wherein the one-week period comprises a treatment cycle and the treatment
cycle is repeated at least twice. In another embodiment, the dose is about 15
mg/m2
to 80 mg/m2. In another embodiment, the dose is about 3 mg/m2 to 24 mg/m2.
[00135] In another aspect, the method of treating solid tumors
comprises
administering a dose of about 15 mg/m2 to 40 mg/m2 of SNS-595 to a patient
once a
week for three weeks followed by a period of at least two weeks where no SNS-
595
is administered to said subject and wherein the cycle is repeated a plurality
of times.
In another embodiment, the dose is about 15 mg/m2 to 35 mg/m2. In another
embodiment, the dose is about 20 mg/m2 to 30 mg/m2. In another embodiment, the
dose is about 20 mg/m2 to 25 mg/m2.
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[00136] In another aspect, the method of treating solid tumors
comprises
administering a dose of about 35 mg/m2 to 80 mg/m2 of SNS-595 to a patient
once
in a three-week period wherein the three week period comprises a treatment
cycle
and the treatment cycle is repeated at least twice.
[00137] In another aspect, a method of treating hematologic
malignancies are
provided herein. Such methods, in certain embodiment, comprise administering a
dose of about 20 mg/m2 to 60 mg/m2 of SNS-595 to a patient.
[00138] In patients who are considered heavily pretreated ("heavily
pretreated
patients"), the method comprises administering a dose of 35 mg/m2 to 60 mg/m2
of
SNS-595 to a patient once in a three week period wherein the three week period
comprises a treatment cycle and the treatment cycle is repeated at least
twice. In
another embodiment, the method for treating a heavily pretreated patient
comprises,
administering a dose of 40 mg/m2 to 50 mg/m2. In another embodiment, the
method
for treating a heavily pretreated patient, comprises administering a dose of
45 mg/m2
to 50 mg/m2. A heavily pretreated patient is defined as described by Tolcher
et al.,
J. Clin. ()Weal. 19: 2937-2947 (2001) and is a patient who has been treated
previously with more than six courses of an alkylating agent-containing
chemotherapy regimen, more than two courses of carboplatin or mitomycin C, any
prior nitrosourea-containing regimen, irradiation to 25% of the bone-marrow
containing areas, high-dose chemotherapy requiring hematopoietic stem-cell
reinfusions, or widespread metastases to bone.
[00139] Patients, who have not been treated previously for their
solid tumors
or have been treated but are not considered heavily pretreated, are minimally
pretreated ("minimally pretreated patients"). For treating minimally
pretreated
patients, the method comprises administering a dose of 45 mg/m2 to 80 mg/m2 of
SNS-595 to a patient once in a three week period wherein the three week period
comprises a treatment cycle and the treatment cycle is repeated at least
twice. In
another embodiment, the method for treating a minimally pretreated patient
comprises, administering a dose of 50 mg/m2 to 75 mg/m2. In another
embodiment,
the method for treating a minimally pretreated patient, comprises
administering a
dose of 55 mg/m2 to 70 mg/m2. In another embodiment, the method for treating a
minimally pretreated patient, comprises administering a dose of 55 mg/m2 to 65
mg/m2.
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[00140] In another aspect, a method of treating a hematologic
cancer such as
leukemias and lymphomas is provided. The method comprises:
i) administering a dose of 10 mg/m2-50 mg/m2 of SNS-595 to a
patient;
ii) waiting a period of at least two days where the subject is not
administered any SNS-595;
iii) administering another dose of 10 mg/m2-50 mg/m2 of SNS-
595 to the patient; and,
iv) repeating steps ii)-iii) a plurality of times.
[00141] In one embodiment, the waiting period is six days. In
another
embodiment, the waiting period is two days. In another embodiment, the waiting
period is three days.
[00142] In one embodiment, the method of treating hematologic
malignancy
comprises administering a dose of about 20 mg/m2, 22 mg/m2, 25 mg/m2, 27 mg/m2
or 30 mg/m2 of SNS-595 to a patient once a week wherein the one-week period
comprises a treatment cycle and the treatment cycle is repeated at least
twice. In one
embodiment, the method of treating hematologic malignancy comprises
administering a dose of about 25 mg/m2 of SNS-595 to a patient once a week
wherein the one-week period comprises a treatment cycle and the treatment
cycle is
repeated at least twice.
[00143] Other dosing schedules useful for treatment of patients
with
hematologic malignacies can include about 25 mg/m2 to about 50 mg/m2
administered twice a week for two weeks. In another embodiment, the dosing
schedules use in treatment of hematologic malignancies include about 30 mg/m2
to
about 45 mg/m2 administered twice a week for two weeks. In another embodiment,
the dosing schedules for treatment of hematologic malignancies include 30, 35,
40,
or 45 mg/m2 administered twice a week for two weeks.
[00144] In one embodiment, the method of treating hematologic
malignancy
comprises administering a dose of about 40 mg/m2, 45 mg/m2, 50 mg/m2, 55 mg/m2
or 60 mg/m2 of SNS-595 to a patient once in two weeks wherein the two-week
period comprises a treatment cycle. In one embodiment, the method of treating
hematologic malignancy comprises administering a dose of about 50 mg/m2 of SNS-
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595 to a patient once in two weeks wherein the two-week period comprises a
treatment cycle.
6.5 COMBINATION THERAPY
[00145] In the methods and compositions provided herein, SNS-595 can
be
used with or combined with other pharmacologically active compounds ("second
active agents"). It is believed that certain combinations work synergistically
in the
treatment of particular types of cancers. SNS-595 can also work to alleviate
adverse
effects associated with certain second active agents, and some second active
agents
can be used to alleviate adverse effects associated with SNS-595.
6.5.1 Second active agents
[00146] One or more second active ingredients or agents can be used
in the
methods and compositions provided herein together with SNS-595. Second active
agents can be large molecules (e.g., proteins) or small molecules (e.g.,
synthetic
inorganic, organometallic or organic molecules).
[00147] 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
artificially made 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. Others 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-nl, interferon alfa-
n3, interferon
beta-I a, and interferon gamma-I b; GM-CF and GM-CSF; and EPO.
[00148] Particular proteins that can be used in the methods and
compositions
include, but are not limited to: filgrastim, which is sold in the United
States under
the trade name Neupogen (Amgen, Thousand Oaks, CA) and its derivatives
including, but not limited to pegfilgrastim; sargramostim, which is sold in
the United
States under the trade name Leukine (Immunex, Seattle, WA); recombinant EPO,
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CA 02620915 2013-04-19
which is sold in the United States under the trade name Epogen6 (Amgen,
Thousand Oaks, CA); epoetin alfa; and darbepoetin alfa.
[00149] Recombinant and mutated forms of GM-CSF can be prepared as
described in U.S. patent nos. 5,391,485; 5,393,870 and 5,229,496.
Recombinant and mutated forms of G-CSF can be
prepared as described in U.S. patent nos. 4,810,643; 4,999,291; 5,528,823 and
5,580,755.
[00150] 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 to the protein or active portion of the protein of
interest.
See, e.g., Penichet, M.L. and Morrison, S.L., J. Inununol. Methods 248:91-101
(2001).
[00151] 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 (Herceptine), rituximab (Rituxane), bevacizumab
(Avastinrm), pertuzumab (Omnitargrm), tositumomab (Beam?), edrecolomab
(Panore", and G250. SNS-595 can also be combined with or used in combination
with, anti-1NF-a antibodies, and/or anti-EGFR antibodies such as, for example,
Erbituxe or panitumumab.
[00152] Large molecule active agents may be Administered in the form of
anti-cancer vaccines. For example, vaccines that secrete or cause the
secretion of,
cytoldnes 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).
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[00153] In contrast to the general rule that drugs with different
mechanism of
actions be selected to maximize the likelihood for additivity or synergy (see
e.g.,
Page, R. and Takimoto, C., "Principles of Chemotherapy", Cancer Management: A
Multidisciplinary Approach (2001), P. 23), combinations comprising SNS-595 and
a
second agent that also impedes DNA synthesis were found to be additive or
synergistic.
[00154] As used herein, an agent impedes DNA synthesis when it
directly or
indirectly affects a cell's ability to synthesize DNA or to repair DNA damage.
The
agent can directly interact with DNA (e.g., bind to or intercalate with) or it
can bind
to a DNA-binding protein that is involved in DNA synthesis or DNA repair. In
general, an agent that impedes DNA synthesis is active during the S phase but
need
not be S phase specific.
[00155] Since SNS-595 affects the DNA-PK pathway, second agent may
be
an agent that mediates its cytotoxicity through the DNA-PK pathway. One
examples is an agent that inhibits non-homologous endjoining repair such as
DNA-
PK inhibitors. As used herein, and unless otherwise indicated, the term "DNA-
PK
inhibitor" means an agent that inhibits or interferes with a signaling pathway
mediated by DNA-PK. The inhibition of the activity of DNA-PK may be direct
(e.g., a catalytic inhibitor of DNA-PK itself) or indirect (e.g., an agent
that interferes
with the formation of the active DNA-PK complex (DNA-PK, Ku70 and Ku80)).
Other examples include, but are not limited to, ligase IV inhibitors and
apoptosis
enhancing agents such as, but not limited to, caspase-9 activators, caspase-3
activators, and Hsp90 inhibitors.
[00156] 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.
[00157] Examples of anti-cancer agents include, but are not limited
to,
alkylating agents, anti-neoplastic agents, anti-metabolites (e.g., folate
analogs,
purine analogs, adenosine analogs, pyrimidine analogs, and substituted ureas),
platinum coordination complexes, topoisomerase II inhibitors, and radiation.
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[00158] Specific anticancer agents incldue, but are not limited to:
acivicin;
aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin;
altretamine;
ambomycin; ametantrone acetate; amsacrine; anastrozole; anthramycin;
asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat;
benzodepa;
bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin;
bleomycin
sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone;
capecitabline; caracemide; carbetimer; carboplatin; carmustine; carubicin
hydrochloride; carzelesin; cedefingol; celecoxib (COX-2 inhibitor);
chlorambucil;
cirolemycin; cisplatin; cladribine; crisnatol mesylate; cyclophosphamide;
cytarabine;
dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine;
dexormaplatin;
dezaguanine; dezaguanine mesylate; diaziquone; docetaxel; doxorubicin;
doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone
propionate; duazomycin; edatrexate; eflomithine hydrochloride; elsamitrucin;
enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole;
erlotinib;
esorubicin hydrochloride; estramustine; estramustine phosphate sodium;
etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole
hydrochloride;
fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil;
flurocitabine; fosquidone; fostriecin sodium; gefitinib; gemcitabine;
gemcitabine
hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine;
iproplatin; irinotecan; irinotecan hydrochloride; lanreotide acetate;
letrozole;
leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine;
losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine
hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril;
mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa;
mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin;
mitosper;
mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole;
nogalamycin; ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomycin;
pemetrexed; pentamustine; peplomycin sulfate; perfosfamide; pipobroman;
piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer
sodium;
porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin
hydrochloride; pyrazofurin; riboprine; safingol; safingol hydrochloride;
semustine;
simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride;
spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur;
talisomycin;
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tecogalan sodium; taxotere; tegafur; teloxantrone hydrochloride; temoporfm;
teniposide; teroxirone; testolactone; thiamiprine; thioguanidine; thioguanine;
thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate;
triciribine
phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole
hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine
sulfate;
vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate;
vinglycinate
sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;
vinzolidine
sulfate; vorozole; zeniplatin; zinostatin; and zorubicin hydrochloride.
1001591 Other anti-cancer drugs include, but are not limited to: 20-
epi-1,25
dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene;
adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine;
ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine;
anagrelide; anastrozole; 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; asulacrine; atamestane;
atrimustine;
axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine;
baccatin
III derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorins;
benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B;
betulinic acid; bFGF inhibitor; bicalutamide; bisantrene;
bisaziridinylspermine;
bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane;
buthionine
sulfoximine; calcipotriol; calphostin C; camptothecin derivatives;
capecitabine;
carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700;
cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS);
castanospermine; cecropin B; cetrorelix; chlorins; chloroquinoxaline
sulfonamide;
cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole;
collismycin
A; collismycin B; combretastatin A4; combretastatin analogue; conagenin;
crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives;
curacin A;
cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate;
cytolytic
factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;
dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin
B; didox; diethylnorspermine; dihydro-5-azacytidine; dihydrotaxol, 9-;
dioxamycin;
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diphenyl spiromustine; docetaxel; docosanol; dolasetron; doxifluridine;
doxorubicin;
droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine;
edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride;
estramustine
analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide
phosphate;
exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride;
flavopiridol;
flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride;
forfenimex;
formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate;
galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione
inhibitors;
hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;
idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imatinib (e.g.,
Gleevece);
imiquimod; immunostimulant peptides; insulin-like growth factor-1 receptor
inhibitor; interferon agonists; interferons; interleukins; iobenguane;
iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole;
isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N
triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate;
leptolstatin;
letrozole; leukemia inhibiting factor; leukocyte alpha interferon;
leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear
polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum
compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine;
losoxantrone; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic
peptides;
maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin
inhibitors;
matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin;
methioninase;
metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim;
mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast
growth factor-saporin; mitoxantrone; mofarotene; molgramostim;Erbitux, human
chorionic gonadotrophin; monophosphoryl lipid A+myobacterium 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; nisamycin; nitric oxide modulators;
nitroxide antioxidant; nitrullyn; oblimersen (Genasensell); 06-benzylguanine;
octreotide; okicenone; oligonucleotides; onapristone; ondansetron;
ondansetron;
oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin;
oxaunomycin;
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paclitaxel; paclitaxel analogues; paclitaxel derivatives; palauamine;
palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin;
pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium;
pentostatin;
pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin;
phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride;
pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator
inhibitor;
platinum complex; platinum compounds; platinum-triamine complex; porfimer
sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2;
proteasome inhibitors; protein A-based immune modulator; protein kinase C
inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine
phosphatase
inhibitors; purine nucleoside phosphorylase inhibitors; purpurins;
pyrazoloacridine;
pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists;
raltitrexed;
ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-
GAP
inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin;
ribozymes;
RII retinamide; rohitukine; romurtide; roquinimex; rubiginone Bl; ruboxyl;
safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics;
semustine; senescence derived inhibitor 1; sense oligonucleotides; signal
transduction inhibitors; sizofiran; sobuzoxane; sodium borocaptate; sodium
phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic
acid;
spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine;
stipiamide;
stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide
antagonist; suradista; suramin; swainsonine; tallimustine; tamoxifen
methiodide;
tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium;
telomerase
inhibitors; temoporfin; teniposide; tetrachlorodecaoxide; tetrazomine;
thaliblastine;
thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin;
thymopoietin
receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl
etiopurpurin;
tirapazamine; titanocene bichloride; topsentin; toremifene; translation
inhibitors;
tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin;
tropisetron;
turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors;
ubenimex;
urogenital sinus-derived growth inhibitory factor; urokinase receptor
antagonists;
vapreotide; variolin B; velaresol; veramine; verdins; verteporfin;
vinorelbine;
vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and
zinostatin
stimalamer.
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[00160] Specific second active agents include, but are not limited
to,
rituximab, oblimersen (Genasense), remicade, docetaxel, celecoxib, melphalan,
dexamethasone (Decadron6), steroids, gemcitabine, cisplatinum, temozolomide,
etoposide, cyclophosphamide, temodar, carboplatin, procarbazine, gliadel,
tamoxifen, topotecan, methotrexate, Arisa , taxol, taxotere, fluorouracil,
leucovorin,
irinotecan, xeloda, CPT-11, interferon alpha, pegylated interferon alpha
(e.g., PEG
1NTRON-A), capecitabine, cisplatin, thiotepa, fludarabine, carboplatin,
liposomal
daunorubicin, cytarabine, doxetaxol, pacilitaxel, vinblastine, IL-2, GM-CSF,
dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin, busulphan,
preclnisone, bisphosphonate, arsenic trioxide, vincristine, doxorubicin
(Doxile),
paclitaxel, ganciclovir, adriamycin, estramustine sodium phosphate (Emcyte),
sulindac, and etoposide.
[00161] In certain embodiments, the second active agent is
etoposide,
daunomycin, actinomycin D, mitomycin C, cisplatin, carboplatin, pemetrexed,
methotrexate, Ara-C, 5-FU, wortmannin, gemcitabin, geldanamycin or a
combination thereof.
[00162] In other embodiments, the second active agent is a
supportive care
agent. An example of supportive care agent is an antiemetic. Specific
antiemetic
agents include, but are not limited to, phenothiazines, butyrophenones,
benzodiazapines, corticosteroids, serotonin antagonists, cannabinoids, and NKI
receptor antagonists. Examples of phenothiazine antiemetics include, but are
not
limited to, prochlorperazine and trimethobenzamide. Examples of butyophenone
antiemetic include, but are not limited to, haloperidol. Examples of
benzodiazapine
antiemetic include, but are not limited to, lorazepam. Examples of
corticosteroid
antiemetic include, but are not limited to, dexamethasone. Examples of
serotonin
antagonist antiemetic include, but are not limited to, ondansetron,
granisetron, and
dolasetron. Examples of cannabinoid antiemetic include, but are not limited
to,
dronabinol. Examples of NKI receptor antagonists include, but are not limited
to,
aprepitant. Doses and dosing regimens of antiemetic agents should depend on
the
specific indication being treated, age and condition of a patient, and
severity of
adverse effects, and may be adjusted accordingly by those of skill in the art.
Examples of doses and dosing regimens can be found, for example, in The
Physician's Desk Reference.
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6.5.2 Exemplary Methods of Combination Therapy
[00163] 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 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
(60th ed.,
2006).
[00164] 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 1,000 mg, from about 5 to about 500 mg, from about 10 to about 375
mg
or from about 50 to about 200 mg. In one embodiment, the second active agent
is
rituximab, oblimersen (Genasensee), GM-CSF, G-CSF, EPO, taxotere, irinotecan,
dacarbazine, transretinoic acid, topotecan, pentoxifylline, ciprofloxacin,
dexamethasone, vincristine, doxorubicin, COX-2 inhibitor, IL2, IL8, IL18, IFN,
Ara-C, vinorelbine or a combination thereof. In certain embodiments, the
second
active agent is etoposide, daunomycin, actinomycin D, mitomycin C, cisplatin,
carboplatin, pemetrexed, methotrexate, Ara-C, 5-FU, wortmannin, geldanamycin,
gemcitabin or a combination thereof.
[00165] In another embodiment, provided herein are methods of treating,
preventing and/or managing hematologic malignancies, 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 conventional therapy.
[00166] In certain embodiments, the second active agent is co-administered
with SNS-595 or administered with 1-50 hours delay. In certain embodiments,
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SNS-595 is administered first followed by administration with the second
active
agent with 1-50 hours delay. In other embodiments, the second active agent is
administered first followed by administration of SNS-595 with 1-50 hours
delay. In
some embodiment, the delay is 24 hours.
[00167] In one embodiment, SNS-595 can be administered in an amount of
from about 1 to about 75 mg/m2, 1 to about 60 mg/m2, 1 to about 48 mg/m2, 1 to
about 24 mg/m2, 1 to about 50 mg/m2, about 1 to about 40 mg/m2, about 1 to
about
30 mg/m2, about 3 to about 30 mg/m2, about 3 to about 24 mg/m2 alone or in
combination with a second active agent disclosed herein, prior to, during, or
after the
use of conventional therapy.
[00168] In another embodiment, the methods provided herein comprise: a)
administering to a patient in need thereof, a dose of about 1 mg/m2 to 75 mg/
m2 of
SNS-595 and b) administering a therapeutically effective amount of a
supportive
care agent.
[00169] In one embodiment, the second agent is an alkylating agent. In
another embodiment, the alkylating agent is an alkyl sulfonate and the cancer
being
treated is leukemia or lymphoma. In another embodiment, the alkyl sulfonate is
busulfan. In another embodiment, the alkyl sulfonate is busulfan and the
therapeutically effective amount is a daily dose of at least 1 mg. In another
embodiment, the alkyl sulfonate is busulfan and the therapeutically effective
amount
is a daily oral dose of between about 2 mg and 8 mg. In another embodiment,
the
alkyl sulfonate is busulfan and the therapeutically effective amount is a
daily oral
dose of between about 1 mg and about 3 mg.
[00170] In another embodiment, the alkylating agent is a nitrogen mustard
and the cancer being treated is bladder cancer, breast cancer, Hodgkin's
disease,
leukemia, lung cancer, melanoma, ovarian cancer, or testicular cancer. In
another
embodiment, the nitrogen mustard is chlorambucil. In another embodiment, the
nitrogen mustard is chlorambucil and the therapeutically effective amount is
at least
0.1 mg/kg. In another embodiment, the nitrogen mustard is chlorambucil and the
therapeutically effective amount is a daily oral dose of between about 0.1
mg/kg and
about 0.2 mg/kg for three to six weeks. In another embodiment, the nitrogen
mustard is chlorambucil and the therapeutically effective amount is a dose of
0.4
mg/kg every three to four weeks. In another embodiment, the nitrogen mustard
is
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cyclophosphamide. In another embodiment, the nitrogen mustard is
cyclophosphamide and the therapeutically effective amount is an intravenous
dose
of at least 10 mg/kg. In another embodiment, the nitrogen mustard is
cyclophosphamide and the therapeutically effective amount is an intravenous
dose
between about 10 mg/kg and about 15 mg/kg every seven to ten days. In another
embodiment, the nitrogen mustard is cyclophosphamide and the therapeutically
effective amount is an oral daily dose between about 1 mg/kg and about 5
mg/kg. In
another embodiment, the nitrogen mustard is melphalan. In another embodiment,
the nitrogen mustard is melphalan and the therapeutically effective amount is
a daily
oral dose of at least 2 mg. In another embodiment, the nitrogen mustard is
melphalan and the therapeutically effective amount is a daily oral dose of 6
mg for
two to three weeks, no melphalan for two to four weeks and then a daily oral
dose of
between about 2 mg and about 4 mg. In another embodiment, the nitrogen mustard
is melphalan and the therapeutically effective amount is a daily oral dose of
10
mg/m2 for four days every four to six weeks.
[00171] In another embodiment, the alkylating agent is a nitrosourea and
the
cancer being treated is brain tumor, colorectal cancer, Hodgkin's disease,
liver
cancer, lung cancer, lymphoma, or melanoma. In another embodiment, the
nitrosourea is carmustine. In another embodiment, the nitrosourea is
carmustine and
the therapeutically effective amount is at least 150 mg/m2. In another
embodiment,
the nitrosourea is carmustine and the therapeutically effective amount is an
intravenous dose between about 150 mg/m2 and 200 mg/m2 every six to eight
weeks.
[00172] In another embodiment, the alkylating agent is a triazene and the
cancer being treated is Hodgkin's disease, melanoma, neuroblastoma, or soft
tissue
sarcoma. In another embodiment, the triazene is dacarbazine. In another
embodiment, the triazene is dacarbazine and the therapeutically effective
amount is
a daily intravenous dose of between about 2.0 mg/kg and about 4.5 mg/kg for
ten
days every four weeks. In another embodiment, the triazene is dacarbazine and
the
therapeutically effective amount is a daily intravenous dose of 250 mg/m2 for
five
days every three weeks. In another embodiment, the triazene is dacarbazine and
the
therapeutically effective amount is an intravenous dose of 375 mg/m2 every
sixteen
days. In another embodiment, the triazene is dacarbazine and the
therapeutically
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effective amount is an intravenous dose of 150 mg/m2 for five days every four
weeks.
[00173] In another embodiment, the second agent is an anti-neoplastic
antibiotic and the cancer being treated is bladder cancer, breast cancer,
cervical
cancer, head and neck cancer, Hodgkin's disease, leukemia, multiple myeloma,
neuroblastoma, ovarian cancer, sarcoma, skin cancer, testicular cancer, or
thyroid
cancer. In another embodiment, the antibiotic is bleomycin. In another
embodiment, the antibiotic is bleomycin and the therapeutically effective
amount is
at least 10 units/m2. In another embodiment, the antibiotic is bleomycin and
the
therapeutically effective amount is an intravenous, subcutaneous, or
intramuscular
dose of between about 10 units/m2 and about 20 units/m2 weekly or twice
weekly.
In another embodiment, the antibiotic is dactinomycin. In another embodiment,
the
antibiotic is dactinomycin and the therapeutically effective amount is at
least 0.01
mg/kg. In another embodiment, the antibiotic is dactinomycin and the
therapeutically effective amount is a daily intravenous dose of between about
0.010
mg/kg and about 0.015 mg/kg for five days every three weeks. In another
embodiment, the antibiotic is dactinomycin and the therapeutically effective
amount
is an intravenous dose of 2 mg/m2 every three or four weeks. In another
embodiment, the antibiotic is daunorubicin. In another embodiment, the
antibiotic is
daunorubicin and the therapeutically effective amount is at least 30 mg/m2. In
another embodiment, the antibiotic is daunorubicin and the therapeutically
effective
amount is a daily intravenous dose of between about 30 mg/m2 and about 45
mg/m2
for three days. In another embodiment, the antibiotic is a liposomal
preparation of
daunorubicin and the therapeutically effective amount is an intravenous dose
of 40
mg/m2 every two weeks. In another embodiment, the antibiotic is doxorubicin.
In
another embodiment, the antibiotic is doxorubicin and the therapeutically
effective
amount is at least 15 mg/m2. In another embodiment, the antibiotic is
doxorubicin
and the therapeutically effective amount is an intravenous dose of between
about 60
mg/m2 and about 90 mg/m2 every three weeks. In another embodiment, the
antibiotic is doxorubicin and the therapeutically effective amount is a weekly
intravenous dose of between about 15 mg/m2 and about 20 mg/m2. In another
embodiment, the antibiotic is doxorubicin and the therapeutically effective
amount is
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a cycle comprising a weekly intravenous dose of 30 mg/m2 for two weeks
followed
by two weeks of no doxorubicin.
[00174] In another embodiment, the second agent is an anti-
metabolite. In
another embodiment, the anti-metabolite is a folate analog and the cancer
being
treated is breast cancer, head and neck cancer, leukemia, lung cancer, non-
Hodgkin's
lymphoma, or osteosarcoma. In another embodiment, the folate analog is
methotrexate. In another embodiment, the folate analog is methotrexate and the
therapeutically effective amount is at least 2.5 mg. In another embodiment,
the
folate analog is methotrexate and the therapeutically effective amount is a
daily oral
dose of between about 2.5 mg and about 5 mg. In another embodiment, the folate
analog is methotrexate and the therapeutically effective amount is a twice-
weekly
dose of between about 5 mg/m2 and about 25 mg/m2. In another embodiment, the
folate analog is methotrexate and the therapeutically effective amount is a
weekly
intravenous dose of 50 mg/m2 every two to three weeks. In another embodiment,
the folate analog is pemetrexed. In another embodiment, the folate analog is
pemetrexed and the therapeutically effective amount is at least 300 mg/m2. In
another embodiment, the folate analog is pemetrexed and the therapeutically
effective amount is an intravenous dose of between about 300 mg/m2 and about
600
mg/m2 every two or three weeks. In another embodiment, the folate analog is
pemetrexed and the therapeutically effective amount is an intravenous dose of
500
mg/m2 every three weeks.
[00175] In another embodiment, the anti-metabolite is a purine
analog and the
cancer being treated is colorectal cancer, leukemia, or myeloma. In another
embodiment, the purine analog is mercaptopurine. In another embodiment, the
purine analog is mercaptopurine and the therapeutically effective amount is at
least
1.5 mg/kg. In another embodiment, the purine analog is mercaptopurine and the
therapeutically effective amount is a daily oral dose of between about 1.5
mg/kg and
about 5 mg/kg. In another embodiment, the purine analog is thioguanidine. In
another embodiment, the purine analog is thioguanidine and the therapeutically
effective amount is at least 2 mg/kg. In another embodiment, the purine analog
is
thioguanidine and the therapeutically effective amount is a daily oral dose of
between about 2 mg/kg and about 3 mg/kg.
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[00176] In another
embodiment, the anti-metabolite is an adenosine analog
and the cancer being treated is leukemia or lymphoma. In another embodiment,
the
adenosine analog is cladribine. In another embodiment, the adenosine analog is
cladribine and the therapeutically effective amount is at least 0.09 mg/kg. In
another
embodiment, the adenosine analog is cladribine and the therapeutically
effective
amount is a daily intravenous dose of 0.09 mg/kg for seven days. In another
embodiment, the adenosine analog is cladribine and the therapeutically
effective
amount is a daily intravenous dose of 4 mg/m2 for seven days. In another
embodiment, the adenosine analog is pentostatin. In another embodiment, the
adenosine analog is pentostatin and the therapeutically effective amount is 4
mg/m2.
In another embodiment, the adenosine analog is pentostatin and the
therapeutically
effective amount is an intravenous dose of 4 mg/m2 every other week. In
another
embodiment, the adenosine analog is pentostatin and the therapeutically
effective
amount is an intravenous dose of 4 mg/m2 every three weeks.
[00177] In another
embodiment, the anti-metabolite is a pyrimidine analog
and the cancer being treated is bladder cancer, breast cancer, colorectal
cancer,
esophageal cancer, head and neck cancer, leukemia, liver cancer, lymphoma,
ovarian
cancer, pancreatic cancer, skin cancer, or stomach cancer. In another
embodiment,
the pyrimidine analog is cytarabine. In another embodiment, the pyrimidine
analog
is cytarabine and the therapeutically effective amount is at least 100 mg/m2.
In
another embodiment the pyrimidine analog is cytarabine and the therapeutically
effective amount is a daily intravenous dose of 100 mg/m2 for seven days. In
another embodiment, the pyrimidine analog is capecitabine. In another
embodiment,
the pyrimidine analog is capecitabine and the therapeutically effective amount
is at
least a daily dose of 2000 mg/m2. In another embodiment, they pyrimidine
analog is
capecitabine and the therapeutically effective amount is a twice-daily oral
dose of
between about 1200 mg/m2 and about 1300 mg/m2 for 14 days. In another
embodiment, the pyrimidine analog is capecitabine and the therapeutically
effective
amount is a three-week cycle wherein a twice-daily dose of about 1250 mg/m2 is
given for fourteen days followed by one week of rest. In another embodiment,
the
pyrimidine analog is fluorouracil. In another embodiment, the pyrimidine
analog is
fluorouracil and the therapeutically effective amount is at least 10 mg/kg. In
another
example, the pyrimidine analog is fluorouracil and the therapeutically
effective
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amount is a daily intravenous dose of between about 300 mg/m2 and about 500
mg/m2 for at least three days. In another example, the pyrimidine analog is
fluorouracil and the therapeutically effective amount is a daily intravenous
dose of
12 mg/kg for three to five days. In another embodiment, the pyrimidine analog
is
fiuorouracil and the therapeutically effective amount is a weekly intravenous
dose of
between about 10 mg/kg and about 15 mg/kg.
[00178] In another embodiment, the anti-metabolite is a substituted urea
and
the cancer being treated is head and neck cancer, leukemia, melanoma, or
ovarian
cancer. In another embodiment, the substituted urea is hydroxyurea. In another
embodiment, the substituted urea is hydroxyurea and the therapeutically
effective
amount is at least 20 mg/kg. In another embodiment, the substituted urea is
hydroxyurea and the therapeutically effective amount is an oral dose of 80
mg/kg
every three days. In another embodiment, the substituted urea is hydroxyurea
and
the therapeutically effective amount is a daily oral dose of between about 20
mg/kg
and about 30 mg/kg.
[00179] In another embodiment, the second agent is a platinum coordination
complex and the cancer being treated is bladder cancer, breast cancer,
cervical
cancer, colon cancer, head and neck cancer, leukemia, lung cancer, lymphoma,
ovarian cancer, sarcoma, testicular cancer, or uterine cancer. In another
embodiment, the platinum coordination complex is carboplatin. In another
embodiment, the platinum coordination complex is carboplatin and the
therapeutically effective amount is at least 300 mg/m2. In another embodiment,
the
platinum coordination complex is carboplatin and the therapeutically effective
amount is at least 300 mg/m2 every four weeks. In another embodiment, the
platinum coordination complex is carboplatin and the therapeutically effective
amount is 300 mg/m2 every four weeks. In another embodiment, the platinum
coordination complex is carboplatin and the therapeutically effective amount
is at
least 360 mg/m2 every four weeks. In another embodiment, the platinum
coordination complex is cisplatin. In another embodiment, the platinum
coordination complex is cisplatin and the therapeutically effective amount is
at least
20 mg/m2. In another embodiment, the platinum coordination complex is
cisplatin
and the therapeutically effective amount is a daily intravenous dose of 20
mg/m2 for
four to five days every three to four weeks. In another embodiment, the
platinum
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coordination complex is cisplatin and the therapeutically effective amount is
an
intravenous dose of 50 mg/m2 every three weeks. In another embodiment, the
platinum coordination complex is oxaliplatin. In another embodiment, the
platinum
coordination complex is oxaliplatin and the therapeutically effective amount
is at
least 75 mg/m2. In another embodiment, the platinum coordination complex is
oxaliplatin and the therapeutically effective amount is between about 50 mg/m2
and
about 100 mg/m2. In another embodiment, the platinum coordination complex is
oxaliplatin and the therapeutically effective amount is an IV infusion of
between
about 50 mg/m2 and about 100 mg/m2 every two weeks. In another embodiment, the
platinum coordination complex is oxaliplatin and the therapeutically effective
amount is an IV infusion of between about 80 mg/m2 and about 90 mg/m2 every
two
weeks. In another embodiment, the platinum coordination complex is oxaliplatin
and the therapeutically effective amount is a two-hour IV infusion of 85 mg/m2
every two weeks.
[00180] In another embodiment, the second agent is a topoisomerase
II
inhibitor and the cancer being treated is Hodgkin's disease, leukemia, small
cell lung
cancer, sarcoma, or testicular cancer. In another embodiment, the
topoisomerase II
inhibitor is etoposide. In another embodiment, the topoisomerase II inhibitor
is
etoposide and the therapeutically effective amount is at least 35 mg/m2. In
another
embodiment, the topoisomerase II inhibitor is etoposide and the
therapeutically
effective amount is between about 50 mg/m2 and about 100 mg/m2. In another
embodiment, the topoisomerase II inhibitor is etoposide and the
therapeutically
effective amount is an intravenous dose of between about 35 mg/m2 and about 50
mg/m2 a day at least three times in five days every three or four weeks. In
another
embodiment, the topoisomerase II inhibitor is etoposide and the
therapeutically
effective amount is an intravenous dose of between about 50 mg/m2 and about
100
mg/m2 a day at least three times in five days every three or four weeks. In
another
embodiment, the topoisomerase II inhibitor is etoposide and the
therapeutically
effective amount is an oral dose of 100 mg/m2 a day at least three times in
five days
every three or four weeks. In another embodiment, the topoisomerase II
inhibitor is
teniposide. In another embodiment, the topoisomerase II inhibitor is
teniposide and
the therapeutically effective amount is at least 20 mg/m2. In another
embodiment,
the topoisomerase II inhibitor is teniposide and the therapeutically effective
amount
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is a weekly dose of 100 mg/m2. In another embodiment, the topoisomerase II
inhibitor is teniposide and the therapeutically effective amount is a twice
weekly
dose of 100 mg/m2. In another embodiment, the topoisomerase II inhibitor is
teniposide and the therapeutically effective amount is a daily dose of between
about
20 mg/m2 and about 60 mg/m2 for five days. In another embodiment, the
topoisomerase II inhibitor is teniposide and the therapeutically effective
amount is a
daily dose of between about 80 mg/m2 and about 90 mg/m2 for five days.
6.6 PHARMACEUTICAL COMPOSITIONS AND DOSAGE FORMS
[00181] 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 some embodiments, the
compositions
provided herein are acidic compositions (e.g., pH<4). Without being limited by
a
particular theory, acidic compositions provide 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).
[00182] In one embodiment, SNS-595 is administered by an IV injection.
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.
[00183] 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
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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.
[00184] 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.
[00185] 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.
[00186] 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's Pharmaceutical Sciences" by E.W. Martin.
[00187] 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
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desired, can also contain minor amounts of wetting or emulsifying agents, or
pH
buffering agents.
[00188] 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.
[00189] 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
an animal subject, or a mammalian subject, and such as a human subject.
[00190] 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 an 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 lignocamne to ease pain at
the site
of the injection.
[00191] Examples of dosage forms include, but are not limited to:
liquid
dosage forms suitable for parenteral administration to a subject; and sterile
solids
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(e.g., crystalline or amorphous solids) that can be reconstituted to provide
liquid
dosage forms suitable for parenteral administration to a subject.
[00192] 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 's Pharmaceutical Sciences,
20th ed.,
Mack Publishing, Easton PA (2000).
[00193] 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.
[00194] Typical dosage forms provided herein comprise SNS-595 within the
range of about 1 mg/m2 to about 75 mg/m2 per day, or weekly, given as a single
once-a-day dose in the morning or as divided doses throughout the day taken
with
food. Particular dosage forms provided herein have about 1, 3, 6, 9, 12, 15,
18, 21,
24, 27 or 30 mg/m2 of SNS-595.
6.6.1 Parenteral Dosage Forms
[00195] 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
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pharmaceutically acceptable vehicle for injection, suspensions ready for
injection,
and emulsions.
[00196] 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.
[00197] 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. Patent No. 5,134,127.
6.6.2 Topical and Mucosal Dosage Forms
[00198] In certain embodiments, provided herein are transdermal, topical,
and
mucosal dosage forms. Transdermal, topical, and mucosal dosage forms provided
herein include, but are not limited to, ophthalmic solutions, sprays,
aerosols, creams,
lotions, ointments, gels, solutions, emulsions, suspensions, or other forms
known to
one of skill in the art. See, e.g., Remington's Pharmaceutical Sciences, 20th
ed.,
Mack Publishing, Easton PA (2000); and Introduction to Pharmaceutical Dosage
Forms, 4th ed., Lea & Febiger, Philadelphia (1985). Dosage forms suitable for
treating mucosal tissues within the oral cavity can be formulated as
mouthwashes or
as oral gels. Further, transdermal dosage forms include "reservoir type" or
"matrix
type" patches, which can be applied to the skin and worn for a specific period
of
time to permit the penetration of a desired amount of active ingredients.
[00199] Suitable excipients (e.g., carriers and diluents) and other
materials
that can be used to provide topical and mucosal dosage forms encompassed
herein
are well known to those skilled in the pharmaceutical arts, and depend on the
particular tissue to which a given pharmaceutical composition or dosage form
will
be applied. With that fact in mind, typical excipients include, but are not
limited to,
water, acetone, ethanol, ethylene glycol, propylene glycol, butane-1,3-diol,
isopropyl
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myristate, isopropyl palmitate, mineral oil, and mixtures thereof to form
solutions,
emulsions or gels, which are non-toxic and pharmaceutically acceptable.
Moisturizers or humectants can also be added to pharmaceutical compositions
and
dosage forms if desired. Examples of such additional ingredients are well
known in
the art. See, e.g., Remington's Pharmaceutical Sciences, 20th ed., Mack
Publishing,
Easton PA (2000).
[00200] The pH of a pharmaceutical composition or dosage form may also be
adjusted to improve delivery of one or more active ingredients. Similarly, the
polarity of a solvent carrier, its ionic strength, or tonicity can be adjusted
to improve
delivery. Compounds such as stearates can also be added to pharmaceutical
compositions or dosage forms to advantageously alter the hydrophilicity or
lipophilicity of one or more active ingredients so as to improve delivery. In
this
regard, stearates can serve as a lipid vehicle for the formulation, as an
emulsifying
agent or surfactant, and as a delivery-enhancing or penetration-enhancing
agent.
Different salts, hydrates or solvates of the active ingredients can be used to
further
adjust the properties of the resulting composition.
7. EXAMPLES
[00201] Certain embodiments provided herein are illustrated by the
following
non-limiting example.
Example 1: Pharmaceutical Composition Suitable for Injection
or Intravenous Infusion
[00202] 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.
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Example 2: Clinical Trial Data of SNS-595 in Patients with
Advanced Solid Tumor Cancer
[00203] 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 anti-tumor activity in patients with refractory solid tumors.
[00204] SNS-595 was administered to patients with advanced solid
cancers as
an IV infusion over 10 minutes on 2 schedules. In the first schedule (A), a
weekly
dose of SNS-595 was administered for three weeks followed by at least 7 days
off
(qwk x3). In the second schedule (B), a dose of SNS-595 was administered once
every three weeks (q3wk).
[00205] In both schedules, the starting dose of SNS-595 was 3
mg/m2, and
doses were escalated by sequential cohorts of 3. The doses were doubled until
the
first related adverse event at or above Grade 2 or until the first abnormal
lab value.
The doses were then escalated by a modified Fibonacci schema.
[00206] No other therapy, for example mitomycin-C, BCNU,
nitrosourea
drugs or MAb therapy, was given within 42 days of the study.
[00207] In study A, 21 patients (9 male, 12 female) were treated in
6 cohorts
(dose range 3-24 mg/m2/wk). In study B, 41(25 male, 16 female) patients were
treated in 9 cohorts (dose range 3-75 mg/m2/wk). The median ages were 61 yrs
(Study A) and 59 yrs (Study B), sex 12F/9M (Study A), 16F/25M (Study B), all
patients had baseline European Cooperative Oncology Group Performance Status
(ECOG PS) 0-2. Patient eligibility included refractory solid tumors and
adequate
organ fimction. Table 1 provides patient demographics in both the studies.
[00208] Table 1: Patient demographics
qwk x3 q3wk total
n (# treated) 21 41 62
Sex
Male 9 25 34
(43%) (61%) (55%)
Female 12 16 28
(57%) (39%) (45%)
Ethnic Background
Asian 2 (10%) 1(2%) 3 (5%)
Black 2(10%) 4(10%) 6(10%)
Hispanic 0 1 (2%) 1 (2%)
Native 0 2 (5%) 2 (3%)
Hawaiian/
Pacific Islander
White 17 33 50
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I (81%) I (81%) I (81%)
Age (yrs)
Mean 59.3 58.5 58.8
Median 61 59 60
Range 19-81 33-79 19-81
Previous Therapies
MP 9 17 26
(43%) (41%) (42%)
HP 12 24 36
(57%) (59%) (58%)
[00209] Table 2 provides a list of tumor types treated in both the
studies.
Table 2: Tumor types treated
qwk q3wk total
x3
n (# treated) 21 41 62
Ovariari 1 9 10
Colon 3 6 9
NSCLC 0 6 6
Pancreas 3 2 5
Renal 1 4 5
Melanoma 1 3 4
Adeno CA (origin unk) 0 3 3
Breast 2 0 2
Sarcomas 0 3 3
Cholangiocarcinoma 1 1 2
Mesothelioma 2 0 2
Neuroendocrine 1 1 2
Bladder 0 1 1
Leiomyosarcoma 1 1 2
Liposarcoma 1 0 1
Mtillerian 0 1 1
Nasopharyngeal 1 0 1
Salivary Gland 1 0 1
Small Cell Lung Cancer 1 0 1
Spindle Cell Carcinoma 1 0 1
[00210] For patients dosed according to schedule A, PK samples were
collected on treatment Days 1 and 15 and were assayed using noncompartmental
analysis. Plasma SNS-595 concentrations were determined using a validated LC-
MS/MS assay. AUC (area under curve) increased proportionally with dose and
mean AUCInf and ranged between 1.7 and 15 g*hr/ml, respectively, for 3 to 24
mg/m2 dose levels. The terminal half-life is approximately 19 hours. No
evidence
of drug dependent alterations in pharmacokinetic parameters was observed after
3
weekly doses. FIG. 1 depicts the plasma concentrations of SNS-595 over time
among the various patient cohorts. Table 3 provides the pharmacokinetic
parameters for patents dosed according to schedule A.
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Table 3: Average of Week 1 and Week 3 Pharmacokinetic Parameters
Dose n(Week 1, T 1/2 hr Cõ,õõ AUCinf Cloh,
Vasobs
(mg/m2) Week 3) tg/m1 pg=hr/m1 L/hrm2 L/m2
3 7 23.31 0.5771 1.711 1.771 52.7
(4,3) 7.2 0.795 0.20 0.23 18.2 _
6 6 13.51 0.5311 2.091 3.051 51.01
(3,3) 2.2 0.28 0.53 0.84 8.22
12 6 19.91 1.841 6.811 1.871 44.61
(3,3) 5.3 2.7 1.68 0.53 8.53
15 10 26.41 0.8651 10.81 1.591 43.8
(5,5) 15.2 0.318 4.7 0.56 7.90
18 6 15.8 1.691 8.50 2.36 47.191
(4,2) 4.2 0.83 2.86 0.88 8.06
24 1 24.2 0.6 15.2 1.58 50.0
(1,0)
Average 18.51 -- -- 2.221 47.61
4.6 0.58 10.7
Range 10-33 0.6-1.8 2-15 1.4-4.3 30-75
[00211] For patients dosed according to schedule B, pharmacokinetic
parameters were evaluated in 36 patients (21 heavily pretreated and 15
minimally
pretreated) after a single dose of 3 to 75 mg/m2. Clearance (CL), volume of
distribution, and terminal half-life (T1/2) remained unchanged across all
patients up
to 48 mg/m2. In minimally pretreated patients, PK parameters remained
unchanged
up to 75 mg/m2. CL was 2.2 Uhr/m2 (range of 1.0-3.8 L/hr/m2), the volume of
distribution was 53 L/m2 (range of 31-76 L/m2), and the T112 was approximately
21
hr (range of 13-49 hr). Exposure was similar for both heavily and minimally
pretreated patients and increased linearly with doses up to 48 mg/m2. Exposure
for
minimally pretreated patients showed a greater than dose linear AUC (area
under the
curve) at the 60 mg/m2 dose level. Table 4 shows pharmacokinetic parameters
for
patients dosed according to schedule B.
Table 4: Week 3 Pharmacokinetic Parameters
Dose n T 1/2 hr Cmax AUCia Clobs Vssobs
(mg/m2) jig/m1 Agehr/m1 L/hrm2 L/m2
3 3 16.41 0.1391 1.141 2.721 57.71
4.8 0.08 0.26 0.58 8.7
6 2 22.21 0.3471 3.041 1.981 59.8
1.9 0.22 0.32 0.21 0.5
12 3 18.01 2.251 6.32 1.90 45.2
4.1 1.07 0.22 0.07 8.9
24 3 15.71 2.701 12.631 1.911 40.71
3.2 2.57 0.86 0.13 8.8
36 6 22.5 3.381 18.051 2.001 61,4
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Dose ii T % hr Cm. AUCinf Clobs Vssobs
(mg/m2) pg/m1
ftg=hr/m1 L/hrm2 L/m2
14.2 1.92 0.73 0.08 12.8
48 10 26.4 3.081 29.41 1.92 58.8
13.1 1.92 11.34 0.91 14.5
60 8 25.0 3.86 40.71 1.881 48.0
17.9 1.68 23.67 0.88 7.3
75 4 25.0 5.05 46.091 1.65 56.3
4.9 1.72 6.12 0.22 9.4
Average 21.3 2.01 53.21
5.3 0.4 4.1
Range 13-56 0.1-5 1-46 1-3.8 31-76
[00212] In study A, pharmacokinetics were assessed on Days 1 and 15 (after
the first and third doses). As seen in Table 5, SNS-595 shows highly
reproducible
pharmacokinetics and low inter-patient variability. No accumulation or change
in
pharmacokinetic parameters was observed after repeat dosing. Exposure
increased
linearly over an 8-fold dose range (1.6-15 g=hr/mL), clearance (CL), volume
of
distribution (Vss) and T112 averaged 2 Uhr/m2, 48 L/m2, 19 hr, respectively,
and did
not change from Day 1 to 15.
[00213] In study B, pharmacokinetics were assessed on Day 1 after the first
dose; exposure increased linearly over the 24-fold dose range (1.1-46
g=hr/mL),
CL, Vss, and T112 averaged 2 L/hr/m2, 53 L/m2, and 21 hrs, respectively.
[00214] Average pharmacokinetic parameters are provided for both studies in
Table 5.
Table 5: Average of wk 1 and wk 3 Pharmacokinetic
Parameters
qwk x3, qwk x3, q3wk
Week 1 Week 3
20 16 39
Dose Range 3 -24 3 - 18 3 -75
(mg/m2)
AUCinf Range 2 - 15 2 - 7 1 - 46
(ptg=hr/mL)
Tin (hr) SD 22 11 19 8 21 5
Clobs (L/hr/m2) 1.9 0.7 2.2 0.9 2.0 0.4
SD
Vss (L/m2) SD 48 12 47 8 53 4
[00215] FIG. 11 demonstrates dose linearity in Studies A and B.
[00216] Table 6 provides data for hematologic effects observed in the
studies.
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Table 6: Hematologic Effects
U # #
Dose Schedule ANC Febrile
< 500 Neut.
3 mg/m2 qwk x3 4 0 0
6 mg/m2 qwk x3 3 0 0
12 mg/m2 qwk x3 3 0 0
15 mg/m2 qwk x3 6 0 0
18 mg/m2 qwk x3 4 0 0
24 mg/m2 qwk x3 1 0 0
3 mg/m2 q3wk 3 0 0
6 mg/m2 q3wk 3 0 0
12 mg/m2 q3wk 3 0 0
24 mg/m2 q3wk 3 0 0
36 mg/m2 q3wk 6 0 0
48 mg/m2 q3wk 6 1 0
48 mg/m2(HP) q3wk 5 2 0
60 mg/m2 q3wk 8 3 1
75 mg/m2 q3wk 4 0 0
n = number of patients in cohort
*Absolute Neutrophil Count (cells/ L) < 500 lasting more than 7 days
[00217] In the description herein, the term "maximum tolerated dose" or
"MTD" refers to the dose level below a dose of SNS-595 where 2 of 6 patients
experienced dose limiting toxicity (DLT). The term, "heavily pretreated" or
"HP"
patient refers to a patient who has previously received >6 courses of an
alkylating
agent, chemotherapy or >2 courses of platinum, mitomycin-C or any nitrosourea,
or
XRT to >25% of bone. The term, "minimally pretreated" or "MP" patient refers
to a
patient who does not fulfill the HP definition. (See, Tolcher et al, JCO 2001;
19:2937-2947).
[00218] As used herein, dose limiting toxicity (DLT) refers to absolute
neutrophil count (ANC) _<_500 for ---- 7 days or febrile neutropenia or
platelet nadir
<25000 or bleeding or non-hematologic adverse events (AE) -Grade 3 (as
described in Common Terminology Criteria for Adverse Events Version 3.0
(CTCAE v3.0)), wherein adverse events required >14 days dose delay.
[00219] Tables 7-9 provide safety data for both the studies.
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Table 7: Frequent (>10% patients) adverse events
Body System qwk x3 q3wk total
preferred n21 n41 n62
term
Cardiac Disorders
edema 0/4 *
peripheral
Gastrointestinal Disorders
abd pain 1/5 0/8 1/13 (8%)
constipation 0/7 1/12 1/19 (5%)
diarrhea 0/4 0/8 0/12 (0%)
nausea 0/8 2/26 2/34 (6%)
vomiting 0/5 1/17 1/22 (5%)
General Conditions
fatigue 1/4 1/13 2/17
, (12%)
Metabolism & Nutrition Disorders
anorexia 0/7 0/7 (0%)
Musculoskeletal & Connective Tissue
Disorders
backpain 0/7 0/7 (0%)
pain in 0/5
extremity
Nervous System Disorders
dizziness 0/6 0/6 (0%)
headache 0/3 0/8 0/11 (0%)
Skin & Subcutaneous Tissue Disorders
alopecia 0/8 0/8 (0%)
*no. patients with Grade > 3 / no. patients with any Grade
Table 8: Hematologic Effects
Qwk q3wk total
x3
n21 n41 n62
Grade 4
10
Neutropenia 0
(24%) (16%)
(ANC< 500/mm3)
Febrile 1 1
Neutropenia 0 (2%) (2%)
Grade 4
2 2
Thrombocytopenia 0
(5%) (3%)
(< 25,000/mm3)
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Table 9: Serious Adverse Events (SAE) Possibly Related to
Study Drug
SAE preferred CTCAE v3.0 Grade
term
1 patient for each qwk x3 q3wk
of the following
Sepsis not Grade 3
observed
Vomiting not Grade 3
observed
Pneumonia not Grade 3
observed
Febrile Neutropenia not Grade 2
observed
Pancytopenia not Grade 4
observed
Thrombosis not Grade 2
observed
[00220] As seen from the data, neutropenia was the dose limiting
toxicity
(DLT) for both studies. In study A, the dose-limiting toxicity (DLT) of
neutropenia
was seen in the first patient at the 24 mg/m2 level. 5 patients were then
treated at 18
mg/m2 where 2 developed DLT of neutropenia. In study B, for the heavily
pretreated
patients, the dose limiting toxicity (DLT) consisting of Grade 4 neutropenia
for
greater than 7 days was observed at 60 mg/m2. For minimally pretreated
patients,
one dose limiting toxicity was seen at a dose of 75 mg/m2.
[00221] The MTD for study A was 15 mg/m2; the MTD for study B was
48
mg/m2 for heavily pretreated (HP) patients and 60 mg/m2 for minimally
pretreated
(MP) patients.
[00222] For both studies two patients had grade 4 thrombocytopenia;
non-
hematologic toxicities were mostly grade 1/2 without dose-limiting
gastrointestinal
toxicity or neurotoxicity.
[00223] Table 10 provides evidence of clinical activity of SNS-595
for both
the studies. For study A, best responses included one patient that achieved
partial
response (PR) and six that achieved stable disease SD (range 16-24 wks). For
study
B, best responses included one PR and 11 SD (range 18-58 wks). Table 11
provides
details of Partial/Minor Responses (PR/MR) in both the studies.
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Table 10: Evidence of Clinical Activity
Initial Scheduled Tumor Type Weeks Best
Dosage on Response
(mg/m2) Therapy
6 qwk x3 Renal Cell 16 SD
12 qwk x3 Leiomyosarcoma 16 SD
Melanoma 16 SD
15 qwk x3 Mesothelioma 28 PR
Mesothelioma 18 SD
Nasopharyngeal 16 SD
24 qwk x3 Salivary Gland 24 SD
3 q3wk Lung 18 SD
6 q3wk Renal Cell 18 SD
12 q3wk Lung 53 SD
24 q3wk Adenocarcinoma 18 SD
(unknown origin)
36 q3wk Ovarian 18 SD
Colon 33 SD
48 q3wk Ovarian 24 PR
Ovarian 30 SD
Lung 46 SD
60 q3wk Ovarian 33 SD
Neuroendocrine 58 SD
75 q3wk Mtillerian 46 SD
Table 11: Details of Partial/Minor Responses (PR/MR)
Best
Response Tumor Criterion Baseline C2 C4 C6
PR Ovarian CA125 (U/mL) 467 272 176 120
P-aortic node (cm) 1.7 1.6 1.5 1.3
Aortic node (cm) 2.4 2.0 2.2 2.0
Iliac node (cm) 5.5 5.0 4.7 3.9
SD (MR) Nasopharyngeal Rt upper lobe 2.3 1.5 - -
nodule 1 (cm)
Rt upper lobe 1.5 1.3 - -
nodule 2 (cm)
Left upper lobe 1.1 1.0 - -
nodule (cm)
Lingular nodule 1.6 1.5 - -
SD (MR) Ovarian CA125 (U/mL) 567 811 419 274
Liver met (cm) 7.4 6.9 5.7 5.7
Aortic node (cm) 1.7 1.5 1.2 1.8
P-aortic node (cm) 1.8 1.1 1.1 1.2
SD (MR) Ovarian CA125 (U/mL) 50 18 16 15
Rectosigmoid 2.5 0.0 0.0 0.0
(cm)
3 mets unchanged
SD (MR) Mtillerian RML Lung (cm) 3.9 3.9 3.7 2.4
RUL Lung (cm) 4.7 4.5 4.5 5.0
RMLL Lung (cm) 2.5 2.5 2.5 2.6
[00224] Significantly, SNS-595 shows evidence of clinical activity
in patients
with advanced solid cancers including two patients that achieved partial
responses
and seventeen patients that achieved stable disease for over sixteen weeks.
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[00225] As seen from the data, SNS-595 was well tolerated and showed
clinical activity with both once a week and once three weeks dosing. The dose
limiting toxicity was non-cumulative neutropenia. SNS-595 demonstrated
predictable pharmacokinetics with low inter-and intra patient variability. No
change
in pharmacokinetic parameters was observed after repeat dosing.
[00226] Useful doses for treatment of solid tumors in patients in need
thereof
include 48 mg/m2 once in three weeks and 15 mg/m2 weekly as described in this
example.
Example 3: High Content Screening and Microscopy
[00227] Cells were plated as sub-confluent populations and allowed to grow
for 36 hours. Cells were then treated with the compound at the given
concentration
for the given time period. Cells were fixed using 4% formaldehyde and
permeabilized with 0.1% triton. Cells were exposed to primary antibodies for 1
hour
at 25 C at a 1:100 dilution in 10% FBS/PBS (anti-pATM ¨ Chemicon, anti-gH2AX-
Cell Signaling Technology). Cells were exposed to secondary antibodies for 1
hour
at 25 C at a 1:100 dilution in 10% FBS/PBS. Hoechst staining was carried out
in
10% FBS/PBS at 500ng/m1 concentrations. High content screening was carried out
on a Cellomics Arrayscan instrument using the Spot Detector algorithm.
[00228] FIG. 2 shows HCT116 cells that were dosed with various compounds
for 6 hour time periods. Cells were then fixed and analyzed for protein
phosphorylation state (gH2AX images obtained using a fluorescence microscope,
pATM images obtained with the ArrayScan VTi). As seen in the figure, SNS-595
treatment leads to nuclear foci formation.
[00229] FIGs. 3-5 illustrate dependence of foci formation on dose and
time. Cells were then fixed and analyzed for phospho-ATM. Cellomics Arrayscan
software was used to identify foci (FIG. 3, orange spots). Foci quantitation
was
carried out by measuring either foci fluorescent intensity (FIG. 4) or cells
with more
than 2 foci (FIG. 5) as a function of time and SNS-595 concentration.
Example 4: MTT assay and Sensitization treatments
[00230] Cells were plated at 4000 cells per well in a 96 well plate,
incubated
for 24 hours and then treated with compound for 72 hours. Cells were then
incubated
with 5% MTT for 1-2 hours and lysed. MTT was colorimetrically read at 570nm
and EC50's were determined using linear regression analysis.
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[00231] Sensitization was carried out with various chemical treatments.
Cells
were pre-treated for 16 hours with chemical sensitizer before addition of drug
(concentrations were as follows: caffeine, 2mM, DNAPK inhibitor II (make),
10uM,
and wortmannin, 100nM. Data is provided in Table 12. Sensitization was
measured
as the fold decrease in the EC50 for cytotoxicity as measured by an MTT assay.
=
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Table 12 DNA damage sensor dependence of SNS-595
-2ompound DSB Mechanism ATRFLOX1 DNAPKcs(-/- Caffeine3 Cell
Line G2 Arrest4 S-Lag5 Timing of
)2
apoptosis6
SNS-595 Replication 1 10 0.5 HCT-
116 + 0.4
dependent
Etoposide Topoisomerase II 1 7 8
ATRFLOX1 + 0.35
0
Bleomycin Chemical 1 4 10
DNAPKcs(-/- + 0.25
0
)2
Camptothecin Topoisomerase I 5 0.7 6
Caffeine3 0.25 0
0
Replication
0
dependent
1 HCT-116 cells with 6 fold lower ATR levels.
2 M059J (DNAPKcs(-/-)) vs M059K (DNAPKcs(+/+)).
3 HCT-116 cells treated with 2mM caffeine to disrupt both ATM and ATR kinase
activities.
4 FACS analysis, asynchronous cell population.
00
FACS analysis, synchronous cell population.
6 Fraction of cell cycle to achieve 50% maximal caspase-3 activation if dosed
at 30 fold above the EC50 for cytotoxicity.
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[00232] The data indicates that SNS-595 displays a unique PIKK
dependence.
While both ATM/ATR and DNAPK are activated following treatment with SNS-
595, only DNAPK is required for DNA repair and cells are sensitized to SNS-595
only when DNAPKcs activity is diminished. ATM/ATR mediates a G2-checkpoint
arrest. Loss of the G2-checkpoint does not sensitize cells to SNS-595. In
contrast
to SNS-595, all other DSB-inducing agents tested utilize ATM/ATR for repair,
and
display sensitization when either ATM or DNAPK activities are inhibited.
Example 5: Repair of DNA damage in the absence of DNA-
damage sensing kinases ATM and ATR
[00233] HCT-116 cells were treated with 10mM SNS-595 or 10 mM
etopo side for 6 h with or without 2mM caffeine. Compound was then removed and
cells were allowed to recover for 16 hours. Cells were analyzed for gH2AX foci
before and after drug washout. As seen in FIG. 6, DNA damage induced by SNS-
595 is readily repaired in the absence of ATM and ATR. In contrast, other
drugs,
(e.g. Etoposide), utilize ATM and ATR for DNA repair. Caffeine treatment
inhibits
the activities of ATM and ATR, leading to defects in homologous recombination,
nucleotide excision repair, and mismatch repair.
Example 6: Repair of DNA damage in the absence of DNA-
damage sensing kinase DNA-PK
[00234] M059K (wt) and M059J (DNAPKcs(-/-)) cells were treated with
10mM SNS-595 or 10 mM etoposide for 6 hours. Compound was then removed and
cells were allowed to recover for 16 hours. Cells were analyzed for gH2AX foci
before and after drug washout. As seen in FIG. 7, SNS-595 damage is not
effectively repaired in the absence of DNA-PK. By comparison, damage induced
by
other drugs (e.g. Etoposide), is readily repaired.
Example 7: Combination Studies with SNS-595
[00235] Cell lines and Cell Culture: HCT116 and NCI-H460 cell lines
were
obtained from ATCC. SKOV3(p53-/-) and SKOV3(p53+/+) were obtained from the
lab of Dr. George Stark of the Lerner Institute of the Cleveland Clinic. All
cell lines
were cultured in RPMI media supplemented with 10% FBS 1% Sodium Bicarbonate
solution and 1% Antibiotic Solution (Cellgro).
[00236] MTT assay: Cells were plated at 4000 cells per well (except
SKOV3
(p53-/-) which were plated at 8000 cells per well) in a 96 well plate,
incubated for 24
hours and then treated with compound. Compound treatment lasted 72 hours.
Cells
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were then incubated with 5% MTT for 1-2 hours, and lysed. MTT was
colorimetrically read at 570 nm. The fraction of dead cells was determined by
the
following formula:
Fraction of Dead cells = 1 ¨ [Abs of sample well ¨
Avg(Abs of no cell control)]/[Avg(Abs of DMSO only
control) ¨ Avg(abs of no cell control)]
[00237] Scheduling studies: When compounds were dosed with a
schedule
that included a washout, cells were washed with 100111 of fresh warm media for
30
minutes, followed by another wash after 90 minutes.
[00238] Statistical Analysis: The data (Fraction of Dead cells) was
analyzed
using Calculsyn.V2 (Biosoft) and is herein represented as the value of the
Combination Index at Fraction affected (Fa) = 0.5. All data is shown with
error bars
indicating the 95% confidence intervals of the mean value.
[00239] A combination is said to be additive if it yields a
Combination Index
of 0.85-1.2. A combination is said to be synergistic if it yields a
Combination Index
less than 0.85 and a combination is said to be antagonistic if it yields a
Combination
Index of more than 1.2. See FIGs. 8-10.
[00240] As seen in FIGs. 8a-8d, SNS-595 dosed simultaneously with
various
cytotoxics in HCT116 colon carcinoma cell line (8a, 8b and 8c) and H460 lung
cancer cell line 8(d) showed significantly synergistic or at least additive
combination
indices. As seen in FIG. 9, SNS-595 dosed simultaneously with a selection of
DNA
damaging agents and antimetabolites showed no significant change in the
combination index between SKOV3 ovarian cancer cell line with or without p53
expression.
[00241] As seen in FIGs. 10a-10d, SNS-595 might have been
antagonistic
when SNS-595 was co-dosed, or dosed with 24 hours delay, with docetaxel (see,
FIGs. 10a and 10c) and gemcitabin (see, FIGs. 10b and 10d) in HCT116 colon
carcinoma cells. Antagonism might have been reduced by dosing SNS-595 first
(see, FIGS. 10c and 10d, co-dose and 24 hrs) versus dosing the other agents
first
(see, FIGS. 10a and 10b, co-dose and 24 hrs). Additivity or possibly synergy
was
achieved when cells were treated with the first agent, washed and then treated
with
the second agent (see, FIGS. 10a-d, 2 hr wash and 24 hr wash).
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Example 8: MTT cell viability assay-Leukemia Cells:
[00242] The following cell lines were used in this assay: HL-60
(promyelocytic leukemia); Jurkat (T cell leukemia); CCRF-CEM (lymphoblastic
leukemia); CEM/C2 (camptothecan resistant derivative of CCRF-CEM).
[00243] Cells were seeded in 96 wells plates at 3000 cells per well
and
incubated for 16 hours. Compound dilutions were performed in DMSO from 10mM
with 3 fold dilutions. Titrations were diluted 1:100 in media to achieve final
compound concentrations. The 96 well plates were aspirated and compound
dilutions in media were added (100m1/well). MTT analysis was carried out after
72
hours of incubation at 37 C. Briefly, 20m1 of MTT solution was added to each
well. Cells were incubated at 37 C for 1-2 hours. Cells were lysed with the
addition
of 100 ml/well cell lysis buffer and MTT was solubilized overnight at 37 C.
Plates
were read on a spectromax machine with an absorbance measurement at 570nM.
IC50's were calculated (data provided in Table 13) using regression analysis
within
GraphPad Prism. As provided in Table 13, SNS-595 shows potent anti-
proliferative
activity against hematologic cell lines tested.
Table 13: IC50 data for various cell lines
IC50 ng/mL
SNS-
Cell Line 595 Etoposide Doxorubicin Irinotecan
HL-60 53 136 24 905
Jurkat 23 nd Nd nd
CCRF-CEM 18 nd 3 479
CEM/C2 10 nd 17 44400
Example 9: Xenograft models:
[00244] LM3-Jck human malignant lymphoma tumor lobes (2-3mm square)
were transplanted subcutaneously into nude mice. Tumors were allowed to grow
to
approximately 7-14 mm in diameter. Mice were pair-matched into no treatment,
irinotecan (100 mg/kg, IV, q4d x 3), doxorubicin (12 mg/kg, IV, Single shot),
etoposide (12 mg/kg, IV, qld x5), and SNS-595 (25 and 20 mg/kg, IV, q7d x 5)
treatment groups. Acceptable toxicity was defined as a mean group weight loss
of
30% or less and not more than one toxic death among 6 treated animals. Anti-
tumor
activities of the drugs were assessed 21 days after the start of
administration.
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[00245] CCRF-CEM acute lymphoblastic leukemia tumor lobes of 2-3 mm
square were transplanted subcutaneously into nude mice. Tumors were allowed to
grow to approximately 8-20 mm in diameter. Mice were pair-matched into no
treatment, irinotecan (100 mg/kg, IV, q4d x 3), doxorubicin (12 mg/kg, IV, q7d
x 3),
etoposide (12 mg/kg, IV, qldx5), and SNS-595 (25 and 20 mg/kg, IV, q7d x 5)
treatment groups. Acceptable toxicity was defined as a mean group weight loss
of
30% or less and not more than one toxic death among 6 treated animals. Anti-
tumor
activities of the drugs were assessed 20 or 21 days after the start of
administration.
Table 14 provides data for tumor inhibition (TI) and survival rate in the CCRF-
CEM
and LM3-Jck xenograft models.
Table 14: Comparative anti-tumor activity of SNS-595 and other
anti-cancer drugs
CCRF-CEM LM3 - JcK
Treatment Dose IR (%) Survival IR CYO Survival
(mg/kg) Ratio Ratio
20 -* 98.9* 6/6
SNS-595 q7d X3,IV 25 98.1* 6/6* 98.5* __ 6/6
Irinotecan q4d x3, 100 99.7* 5/6 97.7* 6/6
IV
Doxorubicin q7d 12 50.3* 6/6 57.2* 6/6
X3, IV
Etoposide qd X 5, 12 28.3 6/6 3.0 6/6
IV
[00246] As seen from the data in Table 14, SNS-595 administered at
20 and
25 mg/kg shows strong antitumor activity with complete tumor regressions
against
LM-3 Jck malignant lymphoma. Tumor inhibition rate (IR) of SNS-595 was similar
to that of irinotecan and superior to etoposide and doxorubicin in both the
CCRF-
CEM and LM3-Jck xenograft models.
Example 10: Bone Marrow / Cytology assay
[00247] Female CD-1 mice were administered 5, 10, 15, or 20 mg/kg
SNS-
595 intravenously on Day 0 and Day 4. Blood was drawn on days 6, 8, and 12
post
initial injection for hematological analysis. Femurs were extracted on day 6
fixed in
Streck and H&E stained prior to bone marrow cellularity analysis. Two days
after
the second administration of SNS-595, bone marrow isolated from femurs showed
a
dose-dependent reduction in cellularity. At 20 mg/kg, cellularity was reduced
to
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7.5%, while circulating neutrophils were reduced from a pre-dose level of 1244
55
cells/mL to a nadir of 51 24 cells/mL blood on day 8. Absolute neutrophil
counts
subsequently rebounded and soon returned to normal levels. Total WBCs also
reached a nadir on day 8, but returned to normal levels. Dose dependent
decrease in
the hematopoietic bone marrow cellularity is shown in FIG. 14. The FIG. shows
cellularity in bone marrow 6 days post initial injection of SNS-595 at various
doses.
[00248] FIG. 15 shows neutrophil counts from blood samples on days
4, 6, 8,
and 12 post initial injection. As seen in FIG. 16, all SNS-595 dose groups
demonstrated a significant decrease in peripheral neutrophils by day 8. As
seen in
FIG. 17, animals receiving 20 mg/kg injections of SNS-595 had less than 50
cells/ml
on day 8.
[00249] FIG. 18 shows that there is a minor platelet response at day
8 to SNS-
595 injection. FIG. 19 shows percent change in body weight at various times
after
administering SNS-595. FIG. 20 shows bone marrow rebound at day 12 post
injection of 20 mg/kg SNS-595.
Example 11: Clinical Trial Data of SNS-595 in Patients with
Hematologic Malignancies
[00250] SNS-595 was administered to patients with advanced or
refractory
acute leukemias as a slow IV push. Diagnoses included AML (19 patients) and
ALL
(2 patients). All patients had disease refractory to or relapsed from prior
therapy
(median 3 prior regimens (range 1-6)).
[00251] A total of 21 patients (9 female and 12 male; median age =
64 yrs,
range 21-80) were treated in five cohorts using two schedules. In the first
schedule
(A), a weekly dose of SNS-595 was administered for three weeks followed by 7
days off (qwk x3). In the second schedule (B), a dose of SNS-595 was
administered
twice a week for two weeks (biwk x2). The cycle duration, including days off,
was
28 days for both schedules. Schedule A had a total of 3 doses per cycle, and
schedule B had a total of 4 doses per cycle. Additional cycles were permitted
if
patients achieved stable disease or better. The starting dose was 18 mg/m2 on
schedule A and 9 mg/m2 on schedule B, and dosage was escalated by cohort.
Cohorts of 3-6 patients were accrued to doses using a modified Fibonacci
sequence.
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[00252] Pharmacokinetic analyses for SNS-595 were performed on
plasma
samples collected during cycle 1. Table 15 provides certain pharmacokinetic
parameters derived from the study.
Table 15: Pharmacokinetic Parameters
Dose Schedule T Y2 hr AUCior Clobs
Vssobs
(mg/m2) ftg=hr/m
L/hrm2 L/m2
1
18 qwk x3 24 4 8.0 1.4
2.310.4 72121
27 qwk x3 22 10 17.8 5 1.6 0.4 47 21
9* biwk x2 2415 4.3 1.3 2.3 0.7 6512
13.5* biwk x2 21 7 5.912.9 2.511.2 61 6
*Similar PK after Days 4, 8, and 11 administration.
[00253] Plasma SNS-595 concentrations were determined using a
validated
LC-MS/MS assay. Plasma exposures at the first two dose levels for each
schedule
increased linearly, resulting in AUCs of 4.3-17.8 [tghr/mL for 9-27 mg/m2
doses.
CL, Vss and terminal half-lives were similar to those in solid tumor patients,
and
averaged ¨2 L/hr/m2, 58 L/m2, and 23 hr, respectively. Six patients
distributed
across all dosing groups shown in Table 15 experienced greater than 50%
reductions
in peripheral blasts following cycle 1.
[00254] No dose limiting toxicities (DLTs) have been observed up to
27
mg/m2 on the qwk x3 schedule or up to 13.5 mg/m2 on the biwk x2 schedule. Non-
dose limiting toxicities included nausea/vomiting, diarrhea, and mucositis.
Grade 4
neutropenic fever was observed in only one patient.
[00255] Other patient cohorts were administered dosages of 38 mg/m2
and 50
mg/m2, respectively, according to Schedule A (qwk x3). Still other patient
cohorts
were administered dosages of 19 mg/m2 and 25 mg/m2, respectively, according to
Schedule B (biwk x2). Safety data are shown in Table 16.
Table 16: Serious Adverse Events (SAE) Possibly Related to
Study Drug
Event Name CTCAE v3.0 Grade
I patient for each qwk x3 biwk x2
of the following
Pneumonia with Grade 3 not
Neutropenia observed
Infection with Grade 3 not
Neutropenia observed
Neutropenic Fevers not Grade 4
observed
Infection not Grade 3
observed
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[00256] Useful dosing schedules for treatment of hematologic
malignancies
can include from about 50 mg/m2 to about 80 mg/m2 administered once a week for
three weeks, Another dose finding use in treatment of hematologic malignancies
is
about 55 mg/m2 to about 75 mg/m2 administered once a week for three weeks.
Other
doses doses finding use in treatment of hematologic malignancies include 60,
65, 70
or 75 mg/m2 administered once a week for three weeks.
[00257] Other dosing schedules useful for treatment of patients with
hematologic malignacies can include about 25 mg/m2 to about 50 mg/m2
administered twice a week for two weeks. Another dose finding use in treatment
of
hematologic malignancies is about 30 mg/m2 to about 45 mg/m2 administered
twice
a week for two weeks. Other doses finding use in treatment of hematologic
malignancies include 30, 35, 40, or 45 mg/m2 administered twice a week for two
weeks.
[00258] The embodiments of the invention 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.
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