Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
CA 03019682 2018-10-01
1
Description
Title of Invention: TREATMENT OF RENAL CELL
CARCINOMA WITH LEN VATINIB AND EVEROLIMUS
Technical Field
[0001] The present application relates generally to methods of treating
renal cell carcinoma.
Background Art
[0002] Kidney cancer constitutes approximately 3% of all cancers worldwide and
is among
the 10 most common cancers in both men and women. Overall, the lifetime risk
for de-
veloping kidney cancer is about 1.6%, with the risk being higher in men than
in
women. The American Cancer Society estimates that in 2016 there will be about
62,700 new cases (39,650 in males and 23,050 in females) of kidney cancer
diagnosed
in the United States with about 14,240 deaths (9,240 men and 5,000 women).
[0003] Renal cell carcinoma (RCC) represents on average over 90% of all
malignancies of
the kidney that occur in adults. RCC arises from the epithelium of the renal
tubules;
specifically, it originates within the renal cortex from the proximal renal
tubular ep-
ithelium. RCC has a male-to-female preponderance of 1.6:1 and is most common
in
those aged 40-70 years. The incidence of RCC is greater in people of Northern
European ancestry and North Americans than in those of Asian or African
descent.
[0004] Approximately 40% of patients with RCC die because of disease
progression,
making this cancer one of the most lethal malignant tumors. Thus, there is a
great need
for new treatment options for this cancer.
Summary of Invention
[0005] This disclosure relates, in part, to methods of treating a subject
with a RCC with a
combination of lenvatinib or a pharmaceutically acceptable salt thereof and
everolimus, wherein the dosage of one or both components of the combination
treatment is modified upon the occurrence of one or more adverse events in the
treated
subject.
[0006] In a first aspect, the disclosure features a method of treating RCC.
The method
involves administering to a human subject that has a RCC a first dosage
regimen
comprising (i) lenvatinib or a pharmaceutically acceptable salt thereof at a
dose of 18
mg/day and (ii) everolimus at a dose of 5 mg/day. In certain embodiments,
following
or during treatment with the first dosage regimen, the human subject develops
an oc-
currence of a first persistent and intolerable Grade 2 or Grade 3 adverse
reaction or
Grade 4 laboratory abnormality. The method further involves terminating admin-
istration of the first dosage regimen after the occurrence of the first
persistent and in-
tolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory
abnormality and
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administering to the human subject a second dosage regimen comprising
lenvatinib or
a pharmaceutically acceptable salt thereof at a dose of 14 mg/day. In other em-
bodiments, following or during treatment with the first dosage regimen, the
human
subject does not develop an adverse reaction, or develops an occurrence of a
Grade 1
or tolerable Grade 2 adverse reaction. In such embodiments, the method further
involves continuing administration of the first dosage regimen to the human
subject
(i.e., not lowering the dose of the first dosage regimen).
[0007] As used throughout this disclosure, a dosage regimen comprising
lenvatinib or a
pharmaceutically acceptable salt thereof at a specified dose means that
lenvatinib or a
pharmaceutically acceptable salt thereof is present in the dosage regimen at
the
specified dose. Although such a dosage regimen can contain additional
components,
lenvatinib or a pharmaceutically acceptable salt thereof is present only at
the specific
dose listed. Similarly, as used throughout this application, a dosage regimen
comprising everolimus at a specified dose means that everolimus is present in
the
dosage regimen at the specified dose. Although such a dosage regimen can
contain ad-
ditional components, everolimus is present only at the specific dose listed.
The dose of
lenvatinib or a pharmaceutically acceptable salt thereof (e.g., 18 mg, 14 mg,
10 mg, 8
mg, or 6 mg) or everolimus (e.g., 5 mg or 2.5 mg) as used throughout refers to
the dose
of the free form of lenvatinib or everolimus, respectively.
[0008] hi a second aspect, the disclosure provides a method of treating RCC
that involves
administering to a human subject that has a RCC a first dosage regimen
comprising (i)
lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 18
mg/day and (ii)
everolimus at a dose of 5 mg/day. In carrying out this method, the human
subject
develops an occurrence of a first persistent and intolerable Grade 2 or Grade
3 adverse
reaction or Grade 4 laboratory abnormality during or following treatment with
the first
dosage regimen. Thereupon, the method further involves terminating
administration of
the first dosage regimen after the occurrence of the first persistent and
intolerable
Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory abnormality and
admin-
istering to the human subject a second dosage regimen comprising lenvatinib or
a phar-
maceutically acceptable salt thereof at a dose of 14 mg/day. In certain
embodiments,
following or during treatment with the second dosage regimen, the human
subject
develops an occurrence of a second persistent and intolerable Grade 2 or Grade
3
adverse reaction or Grade 4 laboratory. The method further comprises
terminating ad-
ministration of the second dosage regimen after the occurrence of the second
persistent
and intolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory
abnormality
and administering to the human subject a third dosage regimen comprising
lenvatinib
or a pharmaceutically acceptable salt thereof at a dose of 10 mg/day. In other
em-
bodiments, following or during treatment with the second dosage regimen, the
human
CA 03019682 2018-10-01
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subject does not develop an adverse reaction, or develops an occurrence of a
Grade 1
or tolerable Grade 2 adverse reaction. In such embodiments, the method further
involves continuing administration of the second dosage regimen to the human
subject
(i.e., not lowering the dose being given in the second dosage regimen).
[0009] In a third aspect, the disclosure features a method of treating RCC
that involves ad-
ministering to a human subject that has a RCC a first dosage regimen
comprising (i)
lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 18
mg/day and (ii)
everollmus at a dose of 5 mg/day. Following or during therapy with the first
dosage
regimen, the human subject develops an occurrence of a first persistent and
intolerable
Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory abnormality. The
method
further involves terminating administration of the first dosage regimen after
the oc-
currence of the first persistent and intolerable Grade 2 or Grade 3 adverse
reaction or
Grade 4 laboratory abnormality and administering to the human subject a second
dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt
thereof at
a dose of 14 mg/day. Following or during treatment with the second dosage
regimen,
the human subject develops an occurrence of a second persistent and
intolerable Grade
2 or Grade 3 adverse reaction or Grade 4 laboratory. The method further
comprises ter-
minating administration of the second dosage regimen after the occurrence of
the
second persistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade
4
laboratory abnormality and administering to the human subject a third dosage
regimen
comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose
of 10 mg/
day. In certain embodiments, following or during treatment with the third
dosage
regimen, the human subject develops an occurrence of a third persistent and
intolerable
Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory abnormality during
treatment with the third dosage regimen. The method further includes
terminating ad-
ministration of the third dosage regimen after the occurrence of the third
persistent and
intolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory
abnormality and
administering to the human subject a fourth dosage regimen comprising
lenvatinib or a
pharmaceutically acceptable salt thereof at a dose of 8 mg/day. In other
embodiments,
following or during treatment with the third dosage regimen, the human subject
does
not develop an adverse reaction, or develops an occurrence of a Grade 1 or
tolerable
Grade 2 adverse reaction. In such embodiments, the method further involves
continuing administration of the third dosage regimen to the human subject
(i.e., not
lowering the dose being given in the third dosage regimen).
[0010] In a fourth aspect, the disclosure features a method of treating RCC
that involves ad-
ministering to a human subject that has a RCC a first dosage regimen
comprising (i)
lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 18
mg/day and (ii)
everolimus at a dose of 5 mg/day. Following or during therapy with the first
dosage
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regimen, the human subject develops an occurrence of a first persistent and
intolerable
Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory abnormality. The
method
further involves terminating administration of the first dosage regimen after
the oc-
currence of the first persistent and intolerable Grade 2 or Grade 3 adverse
reaction or
Grade 4 laboratory abnormality and administering to the human subject a second
dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt
thereof at
a dose of 14 mg/day. Following or during treatment with the second dosage
regimen,
the human subject develops an occurrence of a second persistent and
intolerable Grade
2 or Grade 3 adverse reaction or Grade 4 laboratory. The method further
comprises ter-
minating administration of the second dosage regimen after the occurrence of
the
second persistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade
4
laboratory abnormality and administering to the human subject a third dosage
regimen
comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose
of 10 mg/
day. Following or during treatment with the third dosage regimen, the human
subject
develops an occurrence of a third persistent and intolerable Grade 2 or Grade
3 adverse
reaction or Grade 4 laboratory abnormality during treatment with the third
dosage
regimen. The method further includes terminating administration of the third
dosage
regimen after the occurrence of the third persistent and intolerable Grade 2
or Grade 3
adverse reaction or Grade 4 laboratory abnormality and administering to the
human
subject a fourth dosage regimen comprising lenvatinib or a pharmaceutically ac-
ceptable salt thereof at a dose of 8 mg/day. In certain embodiments, following
or
during treatment with the fourth dosage regimen, the human subject develops a
fourth
persistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade 4
laboratory
abnormality during treatment with the fourth dosage regimen. The method
further
involves discontinuing administration of the fourth dosage regimen to the
human
subject. In other embodiments, following or during treatment with the fourth
dosage
regimen, the human subject does not develop an adverse reaction, or develops
an oc-
currence of a Grade 1 or tolerable Grade 2 adverse reaction. The method
further
involves continuing administration of the fourth dosage regimen to the human
subject
(i.e., not lowering the dose being given in the fourth dosage regimen).
[0011] The following embodiments apply to all of the above aspects. In
certain em-
bodiments, each of the second dosage regimen, the third dosage regimen, and
the
fourth dosage regimen is not initiated until resolution of an adverse reaction
or toxicity
associated with administration of everolimus.
[0012] In other embodiments, each of the second dosage regimen, the third
dosage regimen,
and the fourth dosage regimen comprises everolimus at a dose of 5 mg/day.
[0013] In some embodiments, each of the second dosage regimen, the third
dosage regimen,
and the fourth dosage regimen comprises everolimus at a dose of 5 mg every
other day.
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[0014] In some embodiments, the second dosage regimen comprises everolimus at
a dose of
5 mg/day, the third dosage regimen comprises everolimus at a dose of 5 mg/day,
and
the fourth dosage regimen comprises either no everolimus or everolimus at a
dose of 5
mg every other day.
[0015] In some embodiments, the second dosage regimen comprises everolimus at
a dose of
5 mg/day, the third dosage regimen comprises everolimus at a dose of 5 mg
every
other day, and the fourth dosage regimen comprises either no everolimus or
everolimus
at a dose of 5 mg every other day.
[0016] In other embodiments, each of the second dosage regimen, the third
dosage regimen,
and the fourth dosage regimen comprises everolimus at a dose of 2.5 mg/day.
[0017] In some embodiments, each of the second dosage regimen, the third
dosage regimen,
and the fourth dosage regimen comprises everolimus at a dose of 2.5 mg every
other
day.
[0018] In some embodiments, the second dosage regimen does not include
everolimus. In
some embodiments, the third dosage regimen does not include everolimus. In
some
embodiments, the fourth dosage regimen does not include everolimus. In other
em-
bodiments, the second dosage regimen and the third dosage regimen does not
include
everolimus. In yet other embodiments, the second dosage regimen and the fourth
dosage regimen does not include everolimus. In certain embodiments, the third
dosage
regimen and the fourth dosage regimen does not include everolimus. In other em-
bodiments, each of the second dosage regimen, the third dosage regimen, and
the
fourth dosage regimen does not include everolimus.
[0019] In a fifth aspect, the disclosure provides a method of treating RCC.
The method
involves administering to a human subject that has a renal cell carcinoma and
severe
renal impairment or severe hepatic impairment, a first dosage regimen
comprising (i)
lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 14
mg/day and (ii)
everolimus at a dose of 2.5 mg/day. During or following treatment with the
first dosage
regimen, the human subject develops an occurrence of a first persistent and
intolerable
Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory abnormality. The
method
involves terminating administration of the first dosage regimen after the
occurrence of
the first persistent and intolerable Grade 2 or Grade 3 adverse reaction or
Grade 4
laboratory abnormality and administering to the human subject a second dosage
regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at
a dose
of 10 mg/day.
[0020] In a sixth aspect, the disclosure features a method of treating RCC.
The method
involves administering to a human subject that has a renal cell carcinoma and
severe
renal impairment or severe hepatic impairment, a first dosage regimen
comprising (i)
lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 14
mg/day and (ii)
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everolimus at a dose of 2.5 mg/day. During or following treatment with the
first dosage
regimen, the human subject develops an occurrence of a first persistent and
intolerable
Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory abnormality. The
method
involves terminating administration of the first dosage regimen after the
occurrence of
the first persistent and intolerable Grade 2 or Grade 3 adverse reaction or
Grade 4
laboratory abnormality and administering to the human subject a second dosage
regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at
a dose
of 10 mg/day. During or following treatment with the second dosage regimen,
the
human subject develops an occurrence of a second persistent and intolerable
Grade 2
or Grade 3 adverse reaction or Grade 4 laboratory abnormality. The method
further
involves terminating administration of the second dosage regimen after the
occurrence
of the second persistent and intolerable Grade 2 or Grade 3 adverse reaction
or Grade 4
laboratory abnormality and administering to the human subject a third dosage
regimen
comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose
of 8 mg/
day.
[00211 In a seventh aspect, the disclosure provides a method of treating
RCC. The method
involves administering to a human subject that has a renal cell carcinoma and
severe
renal impairment or severe hepatic impairment, a first dosage regimen
comprising (i)
lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 14
mg/day and (ii)
everolimus at a dose of 2.5 mg/day. During or following treatment with the
first dosage
regimen, the human subject develops an occurrence of a first persistent and
intolerable
Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory abnormality. The
method
involves terminating administration of the first dosage regimen after the
occurrence of
the first persistent and intolerable Grade 2 or Grade 3 adverse reaction or
Grade 4
laboratory abnormality and administering to the human subject a second dosage
regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at
a dose
of 10 mg/day. During or following treatment with the second dosage regimen,
the
human subject develops an occurrence of a second persistent and intolerable
Grade 2
or Grade 3 adverse reaction or Grade 4 laboratory abnormality. The method
further
involves terminating administration of the second dosage regimen after the
occurrence
of the second persistent and intolerable Grade 2 or Grade 3 adverse reaction
or Grade 4
laboratory abnormality and administering to the human subject a third dosage
regimen
comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose
of 8 mg/
day. During or following treatment with the third dosage regimen, the human
subject
develops an occurrence of a third persistent and intolerable Grade 2 or Grade
3 adverse
reaction or Grade 4 laboratory abnormality. The method further involves
terminating
administration of the third dosage regimen after the occurrence of the third
persistent
and intolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory
abnormality
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and administering to the human subject a fourth dosage regimen comprising
lenvatinib
or a pharmaceutically acceptable salt thereof at a dose of 6 mg/day.
[0022] The following embodiments apply to all of the fifth, sixth, and
seventh aspects
above.
[0023] In one embodiment, the human subject has severe renal impairment and
has a
creatinine clearance [CLcr] less than 30 mL/min as calculated by the Cockroft-
Gault
equation.
[0024] In another embodiment, the human subject has severe hepatic
impairment and has a
liver disease classified in Child-Pugh class C.
[0025] In certain embodiments, each of the second dosage regimen, the third
dosage
regimen, and the fourth dosage regimen is not initiated until resolution of an
adverse
reaction or toxicity associated with administration of everolimus.
[0026] In some embodiments, the second dosage regimen comprises everolimus
at a dose of
2.5 mg/day. In other embodiments, the third dosage regimen comprises
everolimus at a
dose of 2.5 mg/day. In yet other embodiments, the fourth dosage regimen
comprises
everolimus at a dose of 2.5 mg/day. In certain embodiments, the second dosage
regimen and the third dosage regimen, comprises everolimus at a dose of 2.5
mg/day.
In some embodiments, the second dosage regimen and the fourth dosage regimen
comprises everolimus at a dose of 2.5 mg/day. In other embodiments, the third
dosage
regimen and the fourth dosage regimen comprises everolimus at a dose of 2.5
mg/day.
In some embodiments, each of the second dosage regimen, the third dosage
regimen,
and the fourth dosage regimen comprises everolimus at a dose of 2.5 mg/day.
[0027] In some embodiments, the second dosage regimen comprises everolimus at
a dose of
2.5 mg every other day. In other embodiments, the third dosage regimen
comprises
everolimus at a dose of 2.5 mg every other day. In yet other embodiments, the
fourth
dosage regimen comprises everolimus at a dose of 2.5 mg every other day. In
certain
embodiments, the second dosage regimen and the third dosage regimen, comprises
everolimus at a dose of 2.5 mg every other day. In some embodiments, the
second
dosage regimen and the fourth dosage regimen comprises everolimus at a dose of
2.5
mg every other day. In other embodiments, the third dosage regimen and the
fourth
dosage regimen comprises everolimus at a dose of 2.5 mg every other day. In
some
embodiments, each of the second dosage regimen, the third dosage regimen, and
the
fourth dosage regimen comprises everolimus at a dose of 2.5 mg every other
day.
[0028] In some embodiments, the second dosage regimen does not include
everolimus. In
some embodiments, the third dosage regimen does not include everolimus. In
some
embodiments, the fourth dosage regimen does not include everolimus. In other
em-
bodiments, the second dosage regimen and the third dosage regimen does not
include
everolimus. In yet other embodiments, the second dosage regimen and the fourth
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dosage regimen does not include everolimus. In certain embodiments, the third
dosage
regimen and the fourth dosage regimen does not include everolimus. In other em-
bodiments, each of the second dosage regimen, the third dosage regimen, and
the
fourth dosage regimen does not include everolimus.
[0029] In an eighth aspect, the disclosure features a method of treating
RCC. The method
involves administering to a human subject that has a RCC a first dosage
regimen
comprising (i) lenvatinib or a pharmaceutically acceptable salt thereof at a
dose of 18
mg/day and (ii) everolimus at a dose of 5 mg/day. Following or during
treatment with
the first dosage regimen, the human subject develops an occurrence of a first
persistent
and intolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory
abnormality.
The method further involves terminating administration of the first dosage
regimen
after the occurrence of the first persistent and intolerable Grade 2 or Grade
3 adverse
reaction or Grade 4 laboratory abnormality and administering to the human
subject a
second dosage regimen comprising (i) lenvatinib or a pharmaceutically
acceptable salt
thereof at a dose of 14 mg/day; and optionally (ii) everolimus at a dose of 5
mg/day, 5
mg every other day, 2.5 mg/day, or 2.5 mg every other day.
[0030] In a ninth aspect, the disclosure provides a method of treating RCC
that involves ad-
ministering to a human subject that has a RCC a first dosage regimen
comprising (i)
lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 18
mg/day and (ii)
everolimus at a dose of 5 mg/day. In carrying out this method, the human
subject
develops an occurrence of a first persistent and intolerable Grade 2 or Grade
3 adverse
reaction or Grade 4 laboratory abnormality during or following treatment with
the first
dosage regimen. Thereupon, the method further involves terminating
administration of
the first dosage regimen after the occurrence of the first persistent and
intolerable
Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory abnormality and
admin-
istering to the human subject a second dosage regimen comprising (i)
lenvatinib or a
pharmaceutically acceptable salt thereof at a dose of 14 mg/day; and (ii)
optionally
everolimus at a dose of 5 mg/day, 5 mg every other day, 2.5 mg/day, or 2.5 mg
every
other day. Following or during treatment with the second dosage regimen, the
human
subject develops an occurrence of a second persistent and intolerable Grade 2
or Grade
3 adverse reaction or Grade 4 laboratory. The method further comprises
terminating
administration of the second dosage regimen after the occurrence of the second
persistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade 4
laboratory
abnormality and administering to the human subject a third dosage regimen
comprising
(i) lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 10
mg/day, and
optionally (ii) everolimus at a dose of 5 mg/day, 5 mg every other day, 2.5
mg/day, or
2.5 mg every other day.
[0031] In a tenth aspect, the disclosure features a method of treating RCC
that involves ad-
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ministering to a human subject that has a RCC a first dosage regimen
comprising (i)
lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 18
mg/day and (ii)
everolimus at a dose of 5 mg/day. Following or during therapy with the first
dosage
regimen, the human subject develops an occurrence of a first persistent and
intolerable
Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory abnormality. The
method
further involves terminating administration of the first dosage regimen after
the oc-
currence of the first persistent and intolerable Grade 2 or Grade 3 adverse
reaction or
Grade 4 laboratory abnormality and administering to the human subject a second
dosage regimen comprising (i) lenvatinib or a pharmaceutically acceptable salt
thereof
at a dose of 14 mg/day, and optionally (ii) everolimus at a dose of 5 mg/day,
5 mg
every other day, 2.5 mg/day, or 2.5 mg every other day. Following or during
treatment
with the second dosage regimen, the human subject develops an occurrence of a
second persistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade
4
laboratory. The method further comprises terminating administration of the
second
dosage regimen after the occurrence of the second persistent and intolerable
Grade 2 or
Grade 3 adverse reaction or Grade 4 laboratory abnormality and administering
to the
human subject a third dosage regimen comprising (i) lenvatinib or a
pharmaceutically
acceptable salt thereof at a dose of 10 mg/day and optionally (ii) everolimus
at a dose
of 5 mg/day, 5 mg every other day, 2.5 mg/day, or 2.5 mg every other day.
Following
or during treatment with the third dosage regimen, the human subject develops
an oc-
currence of a third persistent and intolerable Grade 2 or Grade 3 adverse
reaction or
Grade 4 laboratory abnormality during treatment with the third dosage regimen.
The
method further includes terminating administration of the third dosage regimen
after
the occurrence of the third persistent and intolerable Grade 2 or Grade 3
adverse
reaction or Grade 4 laboratory abnormality and administering to the human
subject a
fourth dosage regimen comprising (i) lenvatinib or a pharmaceutically
acceptable salt
thereof at a dose of 8 mg/day, and optionally (ii) everolimus at a dose of 5
mg/day, 5
mg every other day, 2.5 mg/day, or 2.5 mg every other day.
[00321 In an eleventh aspect, the disclosure features a method of
treating RCC that involves
administering to a human subject that has a RCC a first dosage regimen
comprising (i)
lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 18
mg/day and (ii)
everolimus at a dose of 5 mg/day. Following or during therapy with the first
dosage
regimen, the human subject develops an occurrence of a first persistent and
intolerable
Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory abnormality. The
method
further involves terminating administration of the first dosage regimen after
the oc-
currence of the first persistent and intolerable Grade 2 or Grade 3 adverse
reaction or
Grade 4 laboratory abnormality and administering to the human subject a second
dosage regimen comprising (i) lenvatinib or a pharmaceutically acceptable salt
thereof
CA 03019682 2018-10-01
at a dose of 14 mg/day, and (ii) everolimus at a dose of 5 mg/day or 5 mg
every other
day. Following or during treatment with the second dosage regimen, the human
subject
develops an occurrence of a second persistent and intolerable Grade 2 or Grade
3
adverse reaction or Grade 4 laboratory. The method further comprises
terminating ad-
ministration of the second dosage regimen after the occurrence of the second
persistent
and intolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory
abnormality
and administering to the human subject a third dosage regimen comprising (i)
lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 10
mg/day, and (ii)
everolimus at a dose of 5 mg/day or 5 mg every other day. Following or during
treatment with the third dosage regimen, the human subject develops an
occurrence of
a third persistent and intolerable Grade 2 or Grade 3 adverse reaction or
Grade 4
laboratory abnormality during treatment with the third dosage regimen. The
method
further includes terminating administration of the third dosage regimen after
the oc-
currence of the third persistent and intolerable Grade 2 or Grade 3 adverse
reaction or
Grade 4 laboratory abnormality and administering to the human subject a fourth
dosage regimen comprising (i) lenvatinib or a pharmaceutically acceptable salt
thereof
at a dose of 8 mg/day, and (ii) everolimus at a dose of 5 mg/day or 5 mg every
other
day.
[0033] In a twelfth aspect, the disclosure features a method of treating
RCC. The method
involves administering to a human subject that has a RCC a first dosage
regimen
comprising (i) lenvatinib or a pharmaceutically acceptable salt thereof at a
dose of 14
mg/day and (ii) everolimus at a dose of 5 mg/day. In certain embodiments,
following
or during treatment with the first dosage regimen, the human subject develops
an oc-
currence of a first persistent and intolerable Grade 2 or Grade 3 adverse
reaction or
Grade 4 laboratory abnormality. The method further involves terminating admin-
istration of the first dosage regimen after the occurrence of the first
persistent and in-
tolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory
abnormality and
administering to the human subject a second dosage regimen comprising
lenvatinib or
a pharmaceutically acceptable salt thereof at a dose of 10 mg/day. In other em-
bodiments, following or during treatment with the first dosage regimen, the
human
subject does not develop an adverse reaction, or develops an occurrence of a
Grade 1
or tolerable Grade 2 adverse reaction. In such embodiments, the method further
involves continuing administration of the first dosage regimen to the human
subject
(i.e., not lowering the dose of the first dosage regimen).
[0034] In a thirteenth aspect, the disclosure provides a method of treating
RCC that involves
administering to a human subject that has a RCC a first dosage regimen
comprising (i)
lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 14
mg/day and (ii)
everolimus at a dose of 5 mg/day. In carrying out this method, the human
subject
CA 03019682 2018-10-01
11
develops an occurrence of a first persistent and intolerable Grade 2 or Grade
3 adverse
reaction or Grade 4 laboratory abnormality during or following treatment with
the first
dosage regimen. Thereupon, the method further involves terminating
administration of
the first dosage regimen after the occurrence of the first persistent and
intolerable
Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory abnormality and
admin-
istering to the human subject a second dosage regimen comprising lenvatinib or
a phar-
maceutically acceptable salt thereof at a dose of 10 mg/day. In certain
embodiments,
following or during treatment with the second dosage regimen, the human
subject
develops an occurrence of a second persistent and intolerable Grade 2 or Grade
3
adverse reaction or Grade 4 laboratory. The method further comprises
terminating ad-
ministration of the second dosage regimen after the occurrence of the second
persistent
and intolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory
abnormality
and administering to the human subject a third dosage regimen comprising
lenvatinib
or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day. In other
em-
bodiments, following or during treatment with the second dosage regimen, the
human
subject does not develop an adverse reaction, or develops an occurrence of a
Grade 1
or tolerable Grade 2 adverse reaction. In such embodiments, the method further
involves continuing administration of the second dosage regimen to the human
subject
(i.e., not lowering the dose being given in the second dosage regimen).
[0035] In a fourteenth aspect, the disclosure features a method of
treating RCC that involves
administering to a human subject that has a RCC a first dosage regimen
comprising (i)
lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 14
mg/day and (ii)
everolimus at a dose of 5 mg/day. Following or during therapy with the first
dosage
regimen, the human subject develops an occurrence of a first persistent and
intolerable
Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory abnormality. The
method
further involves terminating administration of the first dosage regimen after
the oc-
currence of the first persistent and intolerable Grade 2 or Grade 3 adverse
reaction or
Grade 4 laboratory abnormality and administering to the human subject a second
dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt
thereof at
a dose of 10 mg/day. Following or during treatment with the second dosage
regimen,
the human subject develops an occurrence of a second persistent and
intolerable Grade
2 or Grade 3 adverse reaction or Grade 4 laboratory. The method further
comprises ter-
minating administration of the second dosage regimen after the occurrence of
the
second persistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade
4
laboratory abnormality and administering to the human subject a third dosage
regimen
comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose
of 8 mg/
day. In certain embodiments, following or during treatment with the third
dosage
regimen, the human subject develops an occurrence of a third persistent and
intolerable
CA 03019682 2018-10-01
12
Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory abnormality during
treatment with the third dosage regimen. The method further includes
terminating ad-
ministration of the third dosage regimen after the occurrence of the third
persistent and
intolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory
abnormality and
administering to the human subject a fourth dosage regimen comprising
lenvatinib or a
pharmaceutically acceptable salt thereof at a dose of 4 mg/day. In other
embodiments,
following or during treatment with the third dosage regimen, the human subject
does
not develop an adverse reaction, or develops an occurrence of a Grade 1 or
tolerable
Grade 2 adverse reaction. In such embodiments, the method further involves
continuing administration of the third dosage regimen to the human subject
(i.e., not
lowering the dose being given in the third dosage regimen).
[0036] In a fifteenth aspect, the disclosure features a method of treating
RCC that involves
administering to a human subject that has a RCC a first dosage regimen
comprising (i)
lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 14
mg/day and (ii)
everolimus at a dose of 5 mg/day. Following or during therapy with the first
dosage
regimen, the human subject develops an occurrence of a first persistent and
intolerable
Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory abnormality. The
method
further involves terminating administration of the first dosage regimen after
the oc-
currence of the first persistent and intolerable Grade 2 or Grade 3 adverse
reaction or
Grade 4 laboratory abnormality and administering to the human subject a second
dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt
thereof at
a dose of 10 mg/day. Following or during treatment with the second dosage
regimen,
the human subject develops an occurrence of a second persistent and
intolerable Grade
2 or Grade 3 adverse reaction or Grade 4 laboratory. The method further
comprises ter-
minating administration of the second dosage regimen after the occurrence of
the
second persistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade
4
laboratory abnormality and administering to the human subject a third dosage
regimen
comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose
of 8 mg/
day. Following or during treatment with the third dosage regimen, the human
subject
develops an occurrence of a third persistent and intolerable Grade 2 or Grade
3 adverse
reaction or Grade 4 laboratory abnormality during treatment with the third
dosage
regimen. The method further includes terminating administration of the third
dosage
regimen after the occurrence of the third persistent and intolerable Grade 2
or Grade 3
adverse reaction or Grade 4 laboratory abnormality and administering to the
human
subject a fourth dosage regimen comprising lenvatinib or a pharmaceutically ac-
ceptable salt thereof at a dose of 4 mg/day. In certain embodiments, following
or
during treatment with the fourth dosage regimen, the human subject develops a
fourth
persistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade 4
laboratory
CA 03019682 2018-10-01
13
abnormality during treatment with the fourth dosage regimen. In such
embodiments,
the method further involves discontinuing administration of the fourth dosage
regimen
to the human subject. In other embodiments, following or during treatment with
the
fourth dosage regimen, the human subject does not develop an adverse reaction,
or
develops an occurrence of a Grade 1 Or tolerable Grade 2 adverse reaction. In
such em-
bodiments, the method further involves continuing administration of the fourth
dosage
regimen to the human subject (i.e., not lowering the dose being given in the
fourth
dosage regimen).
[0037] The following embodiments apply to the twelfth, thirteenth,
fourteenth, and fifteenth
aspects.
[0038] In one embodiment, the second dosage regimen is not initiated until
the first
persistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade 4
laboratory
abnormality is resolved to tolerable Grade 2, Grade 0-1, or baseline. In one
em-
bodiment, the third dosage regimen is not initiated until the second
persistent and in-
tolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory
abnormality is
resolved to tolerable Grade 2, Grade 0-1, or baseline. In one embodiment, the
fourth
dosage regimen is not initiated until the third persistent and intolerable
Grade 2 or
Grade 3 adverse reaction or Grade 4 laboratory abnormality is resolved to
tolerable
Grade 2, Grade 0-1, or baseline. In another embodiment, the second dosage
regimen is
not initiated until the first persistent and intolerable Grade 2 or Grade 3
adverse
reaction or Grade 4 laboratory abnormality is resolved to tolerable Grade 2,
Grade 0-1,
or baseline and the third dosage regimen is not initiated until the second
persistent and
intolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory
abnormality is
resolved to tolerable Grade 2, Grade 0-1, or baseline. In another embodiment,
the
second dosage regimen is not initiated until the first persistent and
intolerable Grade 2
or Grade 3 adverse reaction or Grade 4 laboratory abnormality is resolved to
tolerable
Grade 2, Grade 0-1, or baseline; the third dosage regimen is not initiated
until the
second persistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade
4
laboratory abnormality is resolved to tolerable Grade 2, Grade 0-1, or
baseline; and the
fourth dosage regimen is not initiated until the third persistent and
intolerable Grade 2
or Grade 3 adverse reaction or Grade 4 laboratory abnormality is resolved to
tolerable
Grade 2, Grade 0-1, or baseline.
[0039] In some embodiments, medical management of each of the first,
second, and third
persistent and intolerable Grade 2 or Grade 3 adverse reactions or Grade 4
laboratory
abnormalities is initiated prior to terminating administration of the dosage
regimen ad-
ministered at the time of onset of the adverse reaction or laboratory
abnormality.
[0040] In certain embodiments, medical management of each of the first,
second, and third
persistent and intolerable Grade 2 or Grade 3 adverse reactions or Grade 4
laboratory
CA 03019682 2018-10-01
14
abnormalities is initiated prior to initiating administration of the dosage
regimen that
occurs after resolution of the adverse reaction or laboratory abnormality to
tolerable
Grade 2, Grade 0-1, or baseline.
[0041] In some embodiments, the first persistent and intolerable Grade 2 or
Grade 3 adverse
reaction or Grade 4 laboratory abnormality is the same as the second and/or
third
persistent and intolerable Grade 201 Grade 3 adverse reaction or Grade 4
laboratory
abnormality.
[0042] In certain embodiments, the first persistent and intolerable Grade 2
or Grade 3
adverse reaction or Grade 4 laboratory abnormality is different from the
second and/or
third persistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade
4
laboratory abnormality.
[0043] In some embodiments, the Grade 2 or Grade 3 adverse reaction is
selected from the
group consisting of Grade 3 hypertension, Grade 2 hypertension, Grade 3
cardiac dys-
function, Grade 2 cardiac dysfunction, Grade 3 arterial tbromboembolic event,
Grade 2
arterial thromboembolic event, Grade 3 proteinuria, Grade 2 proteinuria, Grade
3 renal
failure or impairment, Grade 2 renal failure or impairment, Grade 3 diarrhea,
Grade 2
diarrhea, Grade 3 gastrointestinal perforation or fistula, Grade 2
gastrointestinal per-
foration or fistula, Grade 3 vomiting, Grade 2 vomiting, Grade 3 decreased
appetite,
Grade 2 decreased appetite, Grade 3 fatigue, Grade 2 fatigue, Grade 3 nausea,
Grade 2
nausea, Grade 3 cough, Grade 2 cough, Grade 3 decreased weight, Grade 2
decreased
weight, Grade 3 dehydration, Grade 2 dehydration, Grade 3 thrombocytopenia,
Grade
2 thrombocytopenia, Grade 3 anemia, Grade 2 anemia, Grade 3 acute renal
failure,
Grade 2 acute renal failure, Grade 3 QT/QTc interval prolongation, Grade 2
QT/QTc
interval prolongation, Grade 3 reversible posterior leukoencephalopathy
syndrome
(RPLS), Grade 2 RPLS, Grade 3 hemorrhagic events, Grade 2 hemorrhagic events,
Grade 3 hyperthyroidism, and Grade 2 hyperthyroidism. In some instances, the
Grade
2 or Grade 3 adverse reaction is selected from the group consisting of Grade 3
diarrhea, Grade 2 diarrhea, Grade 3 vomiting, Grade 2 vomiting, Grade 3
nausea,
Grade 2 nausea, Grade 3 proteinuria, and Grade 2 proteinuria.
[0044] In certain embodiments, the Grade 4 laboratory abnormality is
selected from the
group consisting of Grade 4 increase in aspartate aminotransferase, Grade 4
increase in
alanine aminotransferase, Grade 4 increase in alkaline phosphatase, Grade 4 hy-
perkalemia, Grade 4 hypokalemia, Grade 4 hyponatrernia, Grade 4 hypocalcemia,
Grade 4 hypophosphaternia, Grade 4 hyperglycemia, Grade 4
hypertriglyceridemia,
Grade 4 increase in cholesterol, Grade 4 increase in lipase, Grade 4 decrease
in
hemoglobin, Grade 4 decrease in platelet count, and Grade 4 decrease in
lymphocyte
count. In some instances, the Grade 4 laboratory abnormality is selected from
the
group consisting of Grade 4 increase in lipase, Grade 4 hypertriglyceridemia,
Grade 4
CA 03019682 2018-10-01
increase in cholesterol, Grade 4 hypophosphatemia, Grade 4 hyponatremia, and
Grade
4 hypokalemia.
[0045] In certain embodiments, each of the second dosage regimen, the third
dosage
regimen, and the fourth dosage regimen is not initiated until resolution of an
adverse
reaction or toxicity associated with administration of everolimus.
[0046] In other embodiments, each of the second dosage regimen, the third
dosage regimen,
and the fourth dosage regimen comprises everolimus at a dose of 5 mg/day.
[0047] In some embodiments, each of the second dosage regimen, the third
dosage regimen,
and the fourth dosage regimen comprises everolimus at a dose of 5 mg every
other day.
[0048] In some embodiments, the second dosage regimen comprises everolimus at
a dose of
5 mg/day, the third dosage regimen comprises everolimus at a dose of 5 mg/day,
and
the fourth dosage regimen comprises either no everolimus or everolimus at a
dose of 5
mg every other day.
[0049] In some embodiments, the second dosage regimen comprises everolimus at
a dose of
5 mg/day, the third dosage regimen comprises everolimus at a dose of 5 mg
every
other day, and the fourth dosage regimen comprises either no everolimus or
everolimus
at a dose of 5 mg every other day.
[0050] In some embodiments, the second dosage regimen does not include
everolimus. In
some embodiments, the third dosage regimen does not include everolimus. In
some
embodiments, the fourth dosage regimen does not include everolimus. In other
em- =
bodiments, the second dosage regimen and the third dosage regimen does not
include
everolimus. In yet other embodiments, the second dosage regimen and the fourth
dosage regimen does not include everolimus. In certain embodiments, the third
dosage
regimen and the fourth dosage regimen does not include everolimus. In other em-
bodiments, each of the second dosage regimen, the third dosage regimen, and
the
fourth dosage regimen does not include everolimus.
[0051] In a sixteenth aspect, the disclosure provides a method of treating
renal cell
carcinoma in a human subject in need thereof. The method involves
administering to a
human subject that has a renal cell carcinoma a first dosage regimen
comprising (i)
lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 14
mg/day and (ii)
everolimus at a dose of 5 mg/day for a treatment period, wherein the human
subject
does not develop an intolerable Grade 2 or Grade 3 adverse reaction or Grade 4
laboratory abnormality during the treatment period with the first dosage
regimen. The
method further involves terminating administration of the first dosage regimen
after
the treatment period and administering to the human subject a second dosage
regimen
comprising (i) lenvatinib or a pharmaceutically acceptable salt thereof at a
dose of 18
mg/day and (ii) everolimus at a dose of 5 mg/day.
[0052] In some embodiments of this aspect, the human subject develops an
occurrence of a
CA 03019682 2018-10-01
16
first persistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade
4
laboratory abnormality during treatment with the second dosage regimen. The
method
further comprises terminating administration of the second dosage regimen
after the
occurrence of the first persistent and intolerable Grade 2 or Grade 3 adverse
reaction or
Grade 4 laboratory abnormality and administering to the human subject a third
dosage
regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at
a dose
of 14 mg/day. In some instances, the human subject develops an occurrence of a
second persistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade
4
laboratory abnormality during treatment with the third dosage regimen. In such
cases,
the administration of the third dosage regimen is terminated and the human
subject is
administered a fourth dosage regimen comprising lenvatinib or a
pharmaceutically ac-
ceptable salt thereof at a dose of 10 mg/day. In other instances, the human
subject does
not develop an adverse reaction, or develops a Grade 1 or tolerable Grade 2
adverse
reaction. In such instances, the human subject can continue being administered
the
third dosage regimen.
[0053] In some embodiments of the sixteenth aspect, the human subject
develops an oc-
currence of a first persistent and intolerable Grade 2 or Grade 3 adverse
reaction or
Grade 4 laboratory abnormality during treatment with the second dosage
regimen. The
method further comprises terminating administration of the second dosage
regimen
after the occurrence of the first persistent and intolerable Grade 2 or Grade
3 adverse
reaction or Grade 4 laboratory abnormality and administering to the human
subject a
third dosage regimen comprising lenvatinib or a pharmaceutically acceptable
salt
thereof at a dose of 14 mg/day. The human subject develops an occurrence of a
second
persistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade 4
laboratory
abnormality during treatment with the third dosage regimen and the
administration of
the third dosage regimen is terminated and the human subject is administered a
fourth
dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt
thereof at
a dose of 10 mg/day. In certain instances, the human subject develops an
occurrence of
a third persistent and intolerable Grade 2 or Grade 3 adverse reaction or
Grade 4
laboratory abnormality during treatment with the fourth dosage regimen and the
ad-
ministration of the fourth dosage regimen is terminated and the human subject
is ad-
ministered a fifth dosage regimen comprising lenvatinib or a pharmaceutically
ac-
ceptable salt thereof at a dose of 8 mg/day. In other instances, the human
subject does
not develop an adverse reaction, or develops a Grade 1 or tolerable Grade 2
adverse
reaction. In such instances, the human subject can continue being administered
the
fourth dosage regimen.
[0054] In certain embodiments of this aspect, the treatment period with the
first dosage
regimen comprises 28 days.
CA 03019682 2018-10-01
17
[0055] In certain embodiments of this aspect, the treatment period with the
first dosage
regimen consists of 28 days. The following embodiments apply to all of the
above
aspects described above.
[0056] In one embodiment, the second dosage regimen is not initiated until
the first
persistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade 4
laboratory
abnormality is resolved to tolerable Grade 2, Grade 0-1, or baseline. In one
em-
bodiment, the third dosage regimen is not initiated until the second
persistent and in-
tolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory
abnormality is
resolved to tolerable Grade 2, Grade 0-1, or baseline. In one embodiment, the
fourth
dosage regimen is not initiated until the third persistent and intolerable
Grade 2 or
Grade 3 adverse reaction or Grade 4 laboratory abnormality is resolved to
tolerable
Grade 2, Grade 0-1, or baseline. In another embodiment, the second dosage
regimen is
not initiated until the first persistent and intolerable Grade 2 or Grade 3
adverse
reaction or Grade 4 laboratory abnormality is resolved to tolerable Grade 2,
Grade 0-1,
or baseline and the third dosage regimen is not initiated until the second
persistent and
intolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory
abnormality is
resolved to tolerable Grade 2, Grade 0-1, or baseline. In another embodiment,
the
second dosage regimen is not initiated until the first persistent and
intolerable Grade 2
or Grade 3 adverse reaction or Grade 4 laboratory abnormality is resolved to
tolerable
Grade 2, Grade 0-1, or baseline; the third dosage regimen is not initiated
until the
second persistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade
4
laboratory abnormality is resolved to tolerable Grade 2, Grade 0-1, or
baseline; and the
fourth dosage regimen is not initiated until the third persistent and
intolerable Grade 2
or Grade 3 adverse reaction or Grade 4 laboratory abnormality is resolved to
tolerable
Grade 2, Grade 0-1, or baseline.
[0057] In one embodiment, the second dosage regimen is not initiated until
the first
persistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade 4
laboratory
abnormality is resolved to Grade 0-1 or tolerable Grade 2. In one embodiment,
the
third dosage regimen is not initiated until the second persistent and
intolerable Grade 2
or Grade 3 adverse reaction or Grade 4 laboratory abnormality is resolved to
Grade 0-1
or tolerable Grade 2. In one embodiment, the fourth dosage regimen is not
initiated
until the third persistent and intolerable Grade 2 or Grade 3 adverse reaction
or Grade
4 laboratory abnormality is resolved to Grade 0-1 or tolerable Grade 2. In
another em-
bodiment, the second dosage regimen is not initiated until the first
persistent and in-
tolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory
abnormality is
resolved to Grade 0-1 or tolerable Grade 2 and the third dosage regimen is not
initiated
until the second persistent and intolerable Grade 2 or Grade 3 adverse
reaction or
Grade 4 laboratory abnormality is resolved to Grade 0-1 or tolerable Grade 2.
In
CA 03019682 2018-10-01
18
another embodiment, the second dosage regimen is not initiated until the first
persistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade 4
laboratory
abnormality is resolved to Grade 0-1 or tolerable Grade 2; the third dosage
regimen is
not initiated until the second persistent and intolerable Grade 2 or Grade 3
adverse
reaction or Grade 4 laboratory abnormality is resolved to Grade 0-1 or
tolerable Grade
2; and the fourth dosage regimen is not initiated until the third persistent
and in-
tolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory
abnormality is
resolved to Grade 0-1 or tolerable Grade 2.
[0058] In some embodiments, medical management of each of the first,
second, and third
persistent and intolerable Grade 2 or Grade 3 adverse reactions or Grade 4
laboratory
abnormalities is initiated prior to terminating administration of the dosage
regimen ad-
ministered at the time of onset of the adverse reaction or laboratory
abnormality.
[0059] In certain embodiments, medical management of each of the first,
second, and third
persistent and intolerable Grade 2 or Grade 3 adverse reactions or Grade 4
laboratory
abnormalities is initiated prior to initiating administration of the dosage
regimen that
occurs after resolution of the adverse reaction or laboratory abnormality to
tolerable
Grade 2, Grade 0-1, or baseline.
[0060] In certain embodiments, medical management of each of the first,
second, and third
persistent and intolerable Grade 2 or Grade 3 adverse reactions or Grade 4
laboratory
abnormalities is initiated prior to initiating administration of the dosage
regimen that
occurs after resolution of the adverse reaction or laboratory abnormality to
Grade 0-1
or tolerable Grade 2.
[0061] In some embodiments, the first persistent and intolerable Grade 2 or
Grade 3 adverse
reaction or Grade 4 laboratory abnormality is the same as the second and/or
third
persistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade 4
laboratory
abnormality.
[0062] In certain embodiments, the first persistent and intolerable Grade 2
or Grade 3
adverse reaction or Grade 4 laboratory abnormality is different from the
second and/or
third persistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade
4
laboratory abnormality.
[0063] In some embodiments, the Grade 2 or Grade 3 adverse reaction is
selected from the
group consisting of Grade 3 hypertension, Grade 2 hypertension, Grade 3
cardiac dys-
function, Grade 2 cardiac dysfunction, Grade 3 arterial thromboernbolic event,
Grade 2
arterial thromboembolic event, Grade 3 proteinuria, Grade 2 proteinuria, Grade
3 renal
failure or impairment, Grade 2 renal failure or impainnent, Grade 3 diarrhea,
Grade 2
diarrhea, Grade 3 gastrointestinal perforation or fistula, Grade 2
gastrointestinal per-
foration or fistula, Grade 3 vomiting, Grade 2 vomiting, Grade 3 decreased
appetite,
Grade 2 decreased appetite, Grade 3 fatigue, Grade 2 fatigue, Grade 3 nausea,
Grade 2
CA 03019682 2018-10-01
19
nausea, Grade 3 cough, Grade 2 cough, Grade 3 decreased weight, Grade 2
decreased
weight, Grade 3 dehydration, Grade 2 dehydration, Grade 3 thrombocytopenia,
Grade
2 thrombocytopenia, Grade 3 anemia, Grade 2 anemia, Grade 3 acute renal
failure,
Grade 2 acute renal failure, Grade 3 QT/QTc interval prolongation, Grade 2
QT/QTc
interval prolongation, Grade 3 reversible posterior leukoencephalopathy
syndrome
(RPLS), Grade 2 RPLS, Grade 3 hemorrhagic events, Grade 2 hemorrhagic events,
Grade 3 hyperthyroidism, and Grade 2 hyperthyroidism. In some instances, the
Grade
2 or Grade 3 adverse reaction is selected from the group consisting of Grade 3
diarrhea, Grade 2 diarrhea, Grade 3 vomiting, Grade 2 vomiting, Grade 3
nausea,
Grade 2 nausea, Grade 3 proteinuria, and Grade 2 proteinuria.
[0064] In certain embodiments, the Grade 4 laboratory abnormality is
selected from the
group consisting of Grade 4 increase in aspartate aminotransferase, Grade 4
increase in
alanine arninotransferase, Grade 4 increase in alkaline phosphatase, Grade 4
hy-
perkalemia, Grade 4 hypokalernia, Grade 4 hyponatremia, Grade 4 hypocalcemia,
Grade 4 hypophosphatemia, Grade 4 hyperglycemia, Grade 4 hypertriglyceridemia,
Grade 4 increase in cholesterol, Grade 4 increase in lipase, Grade 4 decrease
in
hemoglobin, Grade 4 decrease in platelet count, and Grade 4 decrease in
lymphocyte
count. In some instances, the Grade 4 laboratory abnormality is selected from
the
group consisting of Grade 4 increase in lipase, Grade 4 hypertriglyceridemia,
Grade 4
increase in cholesterol, Grade 4 hypophosphatemia, Grade 4 hyponatremia, and
Grade
4 hypokalemia.
[0065] In certain embodiments, each of the second dosage regimen, the third
dosage
regimen, and the fourth dosage regimen is not initiated until resolution of an
adverse
reaction or toxicity associated with administration of everolimus.
[0066] In some embodiments, the second dosage regimen does not include
everolimus. In
some embodiments, the third dosage regimen does not include everolimus. In
some
embodiments, the fourth dosage regimen does not include everolimus. In other
em-
bodiments, the second dosage regimen and the third dosage regimen does not
include
everolimus. In yet other embodiments, the second dosage regimen and the fourth
dosage regimen does not include everolimus. In certain embodiments, the third
dosage
regimen and the fourth dosage regimen does not include everolimus. In other em-
bodiments, each of the second dosage regimen, the third dosage regimen, and
the
fourth dosage regimen does not include everolimus.
[0067] In certain embodiments, lenvatinib or the pharmaceutically
acceptable salt thereof is
formulated as a capsule.
[0068] In some embodiments, everolimus is formulated as a tablet.
[0069] In certain embodiments, lenvatinib or the pharmaceutically
acceptable salt thereof
and everolimus are administered to the human subject orally.
CA 03019682 2018-10-01
[0070] In some embodiments, the human subject has received a prior vascular
endothelial
growth factor (VEGF)-targeted therapy.
[00711 In some embodiments, lenvatinib or the pharmaceutically acceptable
salt thereof and
everolimus are administered once daily.
[0072] In certain embodiments, lenvatinib or the pharmaceutically
acceptable salt thereof
and everolimus are administered once daily for at least 28 weeks, at least 56
weeks, at
least 84 weeks, at least 112 weeks, at least 140 weeks, or at least 168 weeks.
[0073] In some embodiments, the renal cell carcinoma is an unresectable
advanced renal cell
carcinoma.
[0074] In other embodiments, the renal cell carcinoma is a metastatic renal
cell carcinoma.
[0075] In yet other embodiments, the renal cell carcinoma is an advanced
renal cell
carcinoma (e.g., advanced renal cell carcinoma following a prior anti-
angiogenic
therapy). In certain embodiments, the prior anti-angiogenic therapy is a VEGF-
targeted
therapy.
[00761 In some embodiments, lenvatinib or a pharmaceutically acceptable
salt thereof is
lenvatinib mesylate.
[0077] In certain embodiments, the human subject has a poor MSKCC risk score.
[0078) Unless otherwise defined, all technical and scientific terms used
herein have the same
meaning as commonly understood by one of ordinary skill in the art to which
this
invention belongs. Although methods and materials similar or equivalent to
those
described herein can be used in the practice or testing of the present
invention, the
exemplary methods and materials are described below. All publications, patent
ap-
plications, patents, and other references mentioned herein are incorporated by
reference in their entirety. In case of conflict, the present application,
including def-
initions, will control. The materials, methods, and examples are illustrative
only and
not intended to be limiting.
[0079] Other features and advantages of the invention will be apparent from
the following
detailed description and from the claims.
Brief Description of Drawings
[00801 [fig.11FIG. 1 is a Kaplan-Meier plot of Progression-Free Survival
comparing the three
arms of the study. Arm A = LENVIMA(Registered Trademark) 18 mg + EveroEmus 5
mg (top
line in figure); Arm B = red Trademark) 24 mg (middle line in
figure); and
Arm C = Everolimus 10 mg (bottom line in figure). Hazard ratio is based on a
stratified Cox regression model including treatment as a factor and hemoglobin
and
corrected serum calcium as strata. The Efron method was used for correction of
tied
events. Median survival is based on Kaplan-Meier method and 95% confidence
interval is based on the Greenwood formula using log-log transformation.
CA 03019682 2018-10-01
21
[fig.2]FIG. 2 is a Kaplan-Meier plot of Overall Survival comparing the three
arms of
the study. Arm A = LENVIMA(Registeredrnwicu'ark) 18 mg + Everolimus 5 mg (top
line in
figure); Arm B = LENVIIvIA(Registeved TrademaIk) 24 mg (middle line in
figure); and Arm C
Everolimus 10 mg (bottom line in figure). Hazard ratio is based on a
stratified Cox re-
gression model including treatment as a factor and hemoglobin and corrected
serum
calcium as strata. The Efron method was used for correction of tied events.
Median
survival is based on Kaplan-Meier method and 95% confidence interval is based
on the
Greenwood formula using log-log transformation.
[fig.3]EIG. 3 is a Kaplan-Meier plot of Overall Survival comparing the three
arms of
the study. Arm A = LENVIMA(Registered Trademark) 18 mg + Everolimus 5 mg (top
line in
figure); Arm B = LENVIMA(Registered Trademark) 24 mg (middle line in figure);
and Arm C =
Everolimus 10 nig (bottom line in figure). Hazard ratio is based on a
stratified Cox re-
gression model including treatment as a factor and hemoglobin and corrected
serum
calcium as strata. The Efron method was used for correction of tied events.
Median
survival is based on Kaplan-Meier method and 95% confidence interval is based
on the
Greenwood formula using log-log transformation. The data cut-off date was July
31,
2015.
Description of Embodiments
[0081] This application provides methods of treating a human subject that
has a renal cell
carcinoma (e.g., advanced RCC, unresectable advanced RCC, or metastatic RCC).
The
method involves administering to the subject a combination of everolimus (5
mg) and
lenvatinib or a pharmaceutically acceptable salt thereof (18 mg or 14 mg as a
starting
dose (also a starting dose of 14 mg or 10 mg if the subject has severe renal
or hepatic
impairment)). If the subject develops one or more adverse events as a result
of the
treatment with lenvatinib or a pharmaceutically acceptable salt thereof and/or
everolimus, the application provides modifications of the treatment regimen as
well as
adjusted dosing regimens (reduced doses of one or both lenvatinib and
everolimus). If
the subject does not develop an adverse reaction as a result of administration
of a
starting dose of 14 mg of lenvatinib or a pharmaceutically acceptable salt
thereof in
combination with 5 mg of everolimus, the subject can be up-titrated to a
higher dosage
regimen (e,g., 18 mg of lenvatinib or a pharmaceutically acceptable salt
thereof in
combination with 5 mg of everolimus).
[0082] Renal Cell Carcinoma
Cancers of the kidney account for about 2.5% of the total human cancer burden,
with
approximately 338,000 new cases diagnosed in 2012. They occur in all world
regions,
with a predominance in developed countries. There are several types of kidney
cancer
of which renal cell carcinoma (RCC) is the most common (over 90%). RCC arises
in
CA 03019682 2018-10-01
22
the cells of the proximal renal tubular epithelium of the renal tubules and is
often
asymptomatic, being detected incidentally at imaging investigations when a
person is
being examined for other ailments. Hematuria, pain, and flank mass are the
classic
triad of presenting symptoms, but a large percentage of patients lack all of
these
symptoms and present instead with systemic symptoms including chronic fatigue,
weight loss, abdominal pain, abdominal mass, anorexia, anemia, hypercalcernia,
sleep
disturbances, and recurrent fevers. This cancer shows a clear predominance in
men,
with men representing two-thirds of cases. Approximately 40% of patients with
RCC
die because of disease progression.
[0083] According to the 2004 World Health Organization classification,
several histological
RCC subtypes are recognized including: clear cell RCC, multiocular clear cell
RCC,
papillary RCC, and chromophobe RCC, carcinoma of the collecting ducts of
Bellini,
renal medullary carcinoma, Xpll translocation carcinomas, carcinoma associated
with
neuroblastoma, mucinous tubular and spindle cell carcinoma, papillary adenoma,
on-
cocytomas, and renal cell carcinoma unclassified. In 2013, the classification
working
group of the International Society of Urological Pathology (IS UP) consensus
conference on renal neoplasia suggested the addition of five new well-
characterized
types of renal neoplasms as new distinct epithelial tumors within the
classification
system: tubulocystic RCC, acquired cystic disease-associated RCC, clear cell
(tubulo)
papillary RCC, the MiT family translocation RCCs (in particular t(6;11) RCC),
and
hereditary leiomyomatosis RCC syndrome-associated RCC. In addition, the ISUP
also
suggested three additional types considered as new and emerging entities:
thyroid-like
follicular RCC; succinate dehydrogenase B deficiency-associated RCC; and ALK
translocation RCC. Of the several histological RCC subtypes, clear cell RCC,
papillary
RCC, and chromophobe RCC are the most frequent histological subtypes, together
ac-
counting for more than 90% of all RCCs.
[0084] The staging of RCC is important for determining how best to treat
the disease. RCC
can be staged using the TNM staging system, where the size and extent of the
tumor
(T), involvement of lymph nodes (N) and metastases (M) are classified
separately.
Also, it can use overall stage grouping into stage [-IV, with the 1997
revision of MCC
described below:
Stage I: Tumor of a diameter of 7 cm (approx. 2 3/4 inches) or smaller, and
limited to
the kidney. No lymph node involvement or metastases to distant organs.
Stage 11: Tumor larger than 7 cm but still limited to the kidney. No lymph
node in-
volvement or metastases to distant organs.
Stage III (either of the following): (1) Tumor of any size with involvement of
a
nearby lymph node but no metastases to distant organs. Tumor of this stage may
be
with or without spread to fatty tissue around the kidney, with or without
spread into the
CA 03019682 2018-10-01
23
large veins leading from the kidney to the heart. (2) Tumor with spread to
fatty tissue
around the kidney and/or spread into the large veins leading from the kidney
to the
heart, but without spread to any lymph nodes or other organs.
Stage IV (any of the following): (1) Tumor that has spread directly through
the fatty
tissue and the fascia ligament-like tissue that surrounds the kidney. (2)
Involvement of
more than one lymph node near the kidney. (3) Involvement of any lymph node
not
near the kidney. (4) Distant metastases, such as in the lungs, bone, or brain.
[0085] In certain embodiments, the RCC is an advanced RCC (e.g., advanced
renal cell
carcinoma following a prior anti-angiogenic therapy). In certain instances,
the prior
anti-angiogenic therapy is VEGF-targeted therapy. In other embodiments, the
RCC is
an unresectable advanced RCC. In yet other embodiments, the RCC is a
metastatic
RCC.
[0086] Treatment of RCC can involve surgery to remove part or all of the
kidney (partial
nephre.ctomy or nephrectorny). Surgery is most useful if the cancer is only in
the
kidneys. In the case of metastatic disease, surgical treatment may be an
option
depending on the stage of growth of the tumor and how far the disease has
spread. If
surgery is not a good option for the patient, percutaneous ablation therapies
may be
used such as radio frequency ablation and cryoablation. Another approach to
treatment
of RCC is to use immunotherapy to activate the patient's immune system to
attack the
cancer. A further approach is to use targeted therapies that target growth
factors known
to promote the growth and spread of tumors. These therapies include
nivolurnab,
axitinib, sunitinib, bevacizumab, sorafenib, pazopanib, interferon-a,
temsirolimus,
cabozantinib, everolimus, and lenvatinib.
[0087] This disclosure provides methods of treating different types of RCC
(e.g., those
noted above) using a combination of everolimus and lenvatinib or a
pharmaceutically
acceptable salt thereof.
[0088] Lenvatinib
A number of kinase inhibitors have been developed as antitumor agents. For
example, a group of compounds having inhibitory activity against receptor
tyrosine
kinases, such as vascular endothelial growth factor receptor (VEGFR), are
known to
inhibit angiogenesis and are regarded as a new class of antitumor agents.
Lenvatinib is
a multi-target receptor tyrosine kinase inhibitor that inhibits the kinase
activities of
VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). Lenvatinib also inhibits
other receptor tyrosine kinases that have been implicated in pathogenic
angiogenesis,
tumor growth, and cancer progression in addition to their normal cellular
functions,
including fibroblast growth factor (FGF) receptors FGFR1, FGFR2, FGFR3, and
FGFR4; rearranged during transfection receptor (RET), KIT, and platelet-
derived
growth factor receptor alpha (PDGFRa).
CA 03019682 2018-10-01
24
[0089] The term "lenvatinib" refers to
4-(3-chloro-4(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-
quinolinecarbo
xamide. This compound is disclosed in Example 368 (see, column 270) of U.S.
Patent
No. 7,253,286. U.S. Patent No. 7,253,286 is incorporated by reference in its
entirety
herein. The term "pharmaceutically acceptable salt" is not particularly
restricted as to
the type of salt. Examples of such salts include, but are not limited to,
inorganic acid
addition salt such as hydrochloric acid salt, sulfuric acid salt, carbonic
acid salt, bi-
carbonate salt, hydrobromic acid salt, and hydriodic acid salt; organic
carboxylic acid
addition salt such as acetic acid salt, maleic acid salt, lactic acid salt,
tartaric acid salt,
and trifluoroac,etic acid salt; organic sulfonic acid addition salt such as
methane-
sulfonic acid salt, hydroxymethanesulfonic acid salt, hydroxyethanesulfonic
acid salt,
benzenesulfonic acid salt, toluenesulfonic acid salt, and taurine salt; amine
addition
salt such as trimethylamine salt, triethylamine salt, pyridine salt, procaine
salt, picoline
salt, dicyclohexylamine salt, N,M-dibenzylethylenediamine salt, N-
methylglucamine
salt, diethanolamine salt, triethanolamine salt,
tris(hydroxymethylamino)methane salt,
and phenethylbenzylamine salt; and amino acid addition salt such as arginine
salt,
lysine salt, serine salt, glycine salt, aspartic acid salt, and glutarnic acid
salt. In one em-
bodiment, the pharmaceutically acceptable salt is a methanesulfonic acid salt
("mesylate"). The methanesulfonic acid salt form (i.e., the mesylate) of
lenvatinib is
disclosed in US Patent 7,612,208, which is incorporated by reference herein in
its
entirety. The chemical name of lenvatinib mesylate is
4[3-chIoro-4-(N'-cyclopropylureido)phenoxy]-7-methoxyquirioline-6-carboxamide
methanesulfonate and it chemical structure is provided below:
[Chem.1]
H3G0
H2N
0 = H3G¨S03H
0
SA .1\
GI N N
[0090] Lenvatinib mesylate is also referred to as LENVIMA(Rerstered
Trademark).
[0091] Lenvatinib mesylate is a white to pale reddish yellow powder. It is
slightly soluble in
water and practically insoluble in ethanol (dehydrated). The dissociation
constant (pKa
value) of lenvatinib mesylate is 5.05 at 25 C. The partition coefficient (log
P value) is
3.30.
[0092] Everolirnus
Everolimus is an inhibitor of mammalian target of raparnycin (mTOR), a serine-
CA 03019682 2018-10-01
threonine kinase, downstream of the PI3K/AKT pathway. The mTOR pathway is dys-
regulated in several human cancers. Everolimus binds to an intracellular
protein,
FKBP-12, resulting in an inhibitory complex formation with mTOR complex 1
(mTORC1) and thus inhibition of mTOR kinase activity. Everolimus can reduce
the
activity of S6 ribosomal protein kinase (S6K1) and eukaryotic initiation
factor
4E-binding protein (4E-BPI), downstream effectors of mTOR, involved in protein
synthesis. S6K1 is a substrate of nifORCI and phosphorylates the activation
domain 1
of the estrogen receptor which results in ligand-independent activation of the
receptor.
In addition, everolimus can inhibit the expression of hypcoda-inducible factor
(e.g.,
1-11F-1) and reduce the expression of vascular endothelial growth factor
(VEGF). In-
hibition of mTOR by everolimus has been shown to reduce cell proliferation, an-
giogenesis, and glucose uptake in in vitro and/or in vivo studies.
[0093] The chemical name of everolimus is
(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-1
2-{ (1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyll-l-methylethy11-
1
9,30-dimethoxy-15,17,21,23,29,35-hexamethy1-11,36-dioxa-4-aza-
tricyclo[30.3.1.04.9]
hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentaone.
[0094] The structural formula of everolimus is:
[Chem.2]
cH3
C./õ...C.1k) 0
OCH3
0 H
0 0
oH
H3C
OHO H3C
/ OH
H3C
CH3 0
H3C0 H3k...0
I CH3
CH3
[0095] Everolimus is marketed under the tradename AFINITOR(Registered
Trademark). AFINffoR
(Registered Trademark) tablets are supplied for oral administration and
contain 2.5 mg, 5 mg, 7.5
mg, or 10 mg of everolimus. The tablets also contain anhydrous lactose,
butylated hy-
droxytoluene, crospovidone, hypromellose, lactose monohydrate, and magnesium
stearate as inactive ingredients.
[0096] Everolimus is indicated, inter aLia, for the treatment of adults
with advanced RCC
after failure of treatment with sunitinib or sorafenib.
[0097] Combination Therapy for Treatment of RCC
The present disclosure provides, in part, a combination therapy for treatment
of a
CA 03019682 2018-10-01
26
human subject with RCC. In certain instances, the human subject has advanced
RCC
following one prior anti-angiogenic therapy. In a particular embodiment, the
subject to
be administered the combination therapy has had at least one prior VEGF-
targeted
treatment (e.g., sunitinib, pazopanib, tivozanib, axitinib, sorafenib, or
bevacizumab). In
other words, the combination therapy can be employed as a second-line therapy.
In
certain instances, the best response for the at least one prior VEGF-targeted
therapy
was a complete response. In certain instances, the best response for the at
least one
prior VEGF-targeted therapy was a partial response. In certain instances, the
best
response for the at least one prior VEGF-targeted therapy was stable disease.
In certain
instances, the best response for the at least one prior VEGF-targeted therapy
was pro-
gressive disease. In certain instances, the subject has had at least one prior
VEGF-
targeted treatment and one or more of: a previous checkpoint inhibitor
therapy, a
previous interferon therapy, or a previous radiotherapy. In certain
embodiments, the
subject has had progression of the RCC after the one prior VEGF-targeted
treatment.
In some instances, the subject has had progression of the RCC within 1, 2, 3,
4, 5, 6, 7,
8, 9, 10, 11, or 12 months of stopping the prior VEGF-targeted treatment. In
one em-
bodiment, the subject has had progression of the RCC within 9 months of
stopping the
prior VEGF-targeted treatment.
[0098] The combination therapy involves administering the human subject with
RCC with a
combination of lenvatinib or a pharmaceutically acceptable salt thereof and
everolimus. In certain embodiments, the RCC is an advanced RCC (e.g., advanced
renal cell carcinoma following a prior anti-angiogenic therapy). In certain
instances,
the prior anti-angiogenic therapy is VEGF-targeted therapy. In other
embodiments, the
RCC is an unresectable advanced RCC. In yet other embodiments, the RCC is a
metastatic RCC. In certain embodiments, the RCC in the human subject has one
metastasis. In some embodiments, the RCC in the human subject has two
metastases.
In some embodiments, the RCC in the human subject has three or greater
metastases.
In certain instances, the site of metastasis/metastases is bone, liver, lung,
or lymph
nodes. In certain embodiments, the subject belongs to a favorable intermediate
Memorial Sloan Kettering Cancer Center (MSKCC) risk group. In certain em-
bodiments, the subject belongs to an intermediate MSKCC risk group. In some em-
bodiments, the subject belongs to a poor MSKCC risk group. In some
embodiments,
the subject has an Eastern Cooperative Oncology Group (ECOG) performance
status
of zero. In other embodiments, the subject has an ECOG performance status of
one. In
certain embodiments, the subject has had a previous nephrectomy.
[0099] As shown in Example 1, which describes the results of Phase 2
human clinical trials,
the combination of LENVBAA(Registered Trademark) and everolimus showed a
statistically sig-
nificant and clinically meaningful improvement in progression free survival
(PFS)
CA 03019682 2018-10-01
27
compared with everolimus alone or LENVIMA( giatered Trademark) alone. In
addition,
overall survival was longer after treatment with the combination of
LENVEVIA(Registered
Trademark) and everolimus.
[0100] Administration
The combination therapy of everolimus and lenvatinib or a pharmaceutically ac-
ceptable salt thereof may be administered to the human subject in need thereof
by any
means that the health care provider deems useful. For example, each of these
compounds may be administered via oral, rectal, nasal, topical (including
buccal and
sub-lingual), vaginal or parenteral (including intramuscular, sub-cutaneous,
and in-
travenous) administration, or in a form suitable for administration by
inhalation, in-
sufflation, or transdermal patch. Each compound may be administered in the
same
manner or via different methods. Tablets or capsules for oral administration
and liquids
for intravenous administration are preferred compositions.
[0101] For oral administration, the compound can be in the form of, e.g., a
tablet, capsule,
suspension, or liquid. The pharmaceutical composition is preferably made in
the form
of a dosage unit containing a particular amount of the active ingredient.
Examples of
such dosage units are capsules, tablets, powders, granules or a suspension,
with con-
ventional additives such as lactose, mannitol, corn starch or potato starch;
with binders
such as crystalline cellulose, cellulose derivatives, acacia, corn starch or
gelatins; with
disintegrators such as corn starch, potato starch or sodium carboxymethyl-
cellulose;
and with lubricants such as talc or magnesium stearate. The active
ingredient(s) may
also be administered by injection as a composition wherein, for example,
saline,
dextrose or water may be used as a suitable pharmaceutically acceptable
carrier.
[0102] In one embodiment, lenvatinib mesylate is administered to the human
subject as a
capsule. The capsule can contain, e.g., lenvatinib mesylate equivalent to 1
mg, 2 mg, 3
mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15
mg,
16 mg, 17 mg, 18 mg, 19 mg, or 20 mg of lenvatinib. In certain instances, the
capsule
contains lenvatinib mesylate equivalent to 4 mg lenvatinib. In certain
instances, the
capsule contains lenvatinib mesylate equivalent to 10 mg lenvatinib. In some
em-
bodiments, these capsules also contain one or more of the following inactive
in-
gredients: calcium carbonate, mannitol, microcrystalline cellulose,
hydroxypropyl-
cellulose, hydroxypropyl cellulose (type H), and talc. In some embodiments,
the shell
of these capsules is a hypromellose shell and can contain one or more of:
titanium
dioxide, ferric oxide yellow, and ferric oxide red. The printing ink used on
the capsule
may contain one or more of: shellac, black iron oxide, potassium hydroxide,
and
propylene glycol.
[0103] In certain embodiments, lenvatinib mesylate is administered to the
human subject at a
dose of 18 mg once daily. This dose can be administered, e.g., as one 10 mg
capsule
CA 03019682 2018-10-01
28
and two 4 mg capsules orally once daily. In other embodiments, lenvatinib
mesylate is
administered to the human subject at a dose of 14 mg once daily. This dose can
be ad-
ministered, e.g., as one 10 mg capsule and one 4 mg capsule orally once daily.
In some
embodiments, lenvatinib mesylate is administered to the human subject at a
dose of 10
mg once daily. This dose can be administered, e.g., as one 10 mg capsule
orally once
daily. In some embodiments, lenvatinib mesylate is administered to the human
subject
at a dose of 8 mg once daily. This dose can be administered, e.g., as two 4 mg
capsules
orally once daily. In some embodiments, lenvatinib mesylate is administered to
the
human subject at a dose of 6 mg once daily. In some embodiments, lenvatinib
mesylate
is administered to the human subject at a dose of 4 mg once daily. This dose
can be ad-
ministered, e.g., as one 4 mg capsule orally once daily.
[0104] in one embodiment, everolimus is administered to the human subject
as a tablet. The
tablet can contain, e.g., 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg,
7.5 mg, 8
mg, 9 mg, or 10 mg of everolimus. In certain instances, the everolimus tablets
also
contain inactive ingredient(s). For example, the everolimus tablet may contain
one or
more of: anhydrous lactose, butylated hydroxytoluene, crospovidone,
hypromellose,
lactose monohydrate, and magnesium stearate as inactive ingredients. In one em-
bodiment, everolimus is administered to the human subject as an oral
suspension. The
oral suspension may be made by dissolving an everolimus tablet in a liquid
(e.g.,
water). The everolimus tablets for oral suspension also contain inactive
ingredient(s).
For example, the everolimus tablets for oral suspension can also contain one
or more
of: butylated hydroxytoluene, colloidal silicon dioxide, crospovidone,
hypromellose,
lactose monohydrate, magnesium stearate, mannitol, and microcrystalline
cellulose as
inactive ingredients.
[0105] In certain embodiments, everolimus is administered to the human
subject at a dose of
mg once daily. This dose can be administered, e.g., as one 5 mg tablet orally
once
daily, two 2.5 mg tablets orally once daily; or an oral suspension of a 5 mg
tablet. In
some embodiments, everolimus is administered to the human subject at a dose of
5 mg
once every other day. In some embodiments, everolimus is administered to the
human
subject at a dose of 2.5 mg once daily. In some embodiments, everolimus is ad-
ministered to the human subject at a dose of 2.5 mg once every other day. In
certain
cases, everolimus is discontinued for Grade 3 toxicity.
[0106] In some embodiments, the lenvatinib or a pharmaceutically acceptable
salt thereof
(e.g., lenvatinib mesylate) is administered as a capsule and everolimus is
administered
as a tablet. In one embodiment, lenvatinib or pharmaceutically acceptable salt
thereof
(e.g., lenvatinib mesylate) is administered at a dose of 18 mg once daily and
everolimus is co-administered at a dose of 5 mg once daily. In another
embodiment,
lenvatinib or pharmaceutically acceptable salt thereof is administered at a
dose of 18
CA 03019682 2018-10-01
29
mg once daily and everolimus is co-administered at a dose of 5 mg once every
other
day. In one embodiment, lenvatinib or pharmaceutically acceptable salt thereof
is ad-
ministered at a dose of 18 mg once daily and everolimus is co-administered at
a dose
of 2.5 mg once daily. In another embodiment, lenvatinib or pharmaceutically ac-
ceptable salt thereof is administered at a dose of 18 mg once daily and
everolimus is
co-administered at a dose of 2.5 mg once every other day. In a different
embodiment,
lenvatinib or pharmaceutically acceptable salt thereof (e.g., lenvatinib
mesylate)is ad-
ministered at a dose of 14 mg once daily and everolimus is co-administered at
a dose
of 5 mg once daily. In another embodiment, lenvatinib or pharmaceutically
acceptable
salt thereof is administered at a dose of 14 mg once daily and everolimus is
co-
administered at a dose of 5 mg once every other day. In a another embodiment,
lenvatinib or pharmaceutically acceptable salt thereof is administered at a
dose of 14
mg once daily and everolimus is co-administered at a dose of 2.5 mg once
daily. In
another embodiment, lenvatinib or pharmaceutically acceptable salt thereof is
ad-
ministered at a dose of 14 mg once daily and everolimus is co-administered at
a dose
of 2.5 mg once every other day. In a different embodiment, lenvatinib or
pharma-
ceutically acceptable salt thereof (e.g., lenvatinib mesylate) is administered
at a dose of
mg once daily and everolimus is co-administered at a dose of 5 mg once daily.
In
another embodiment, lenvatinib or pharmaceutically acceptable salt thereof is
ad-
ministered at a dose of 10 mg once daily and everolimus is co-administered at
a dose
of 5 mg once every other day. In another embodiment, lenvatinib or
pharmaceutically
acceptable salt thereof is administered at a dose of 10 mg once daily and
everolimus is
co-administered at a dose of 2.5 mg once daily. In another embodiment,
lenvatinib or
pharmaceutically acceptable salt thereof is administered at a dose of 10 mg
once daily
and everolimus is co-administered at a dose of 2.5 mg once every other day. In
a
different embodiment, lenvatinib or pharmaceutically acceptable salt thereof
(e.g.,
lenvatinib mesylate) is administered at a dose of 8 mg once daily and
everolimus is co-
administered at a dose of 5 mg once daily. In one embodiment, lenvatinib or
pharma-
ceutically acceptable salt thereof is administered at a dose of 8 mg once
daily and
everolimus is co-administered at a dose of 5 mg once every other day. In
another em-
bodiment, lenvatinib or pharmaceutically acceptable salt thereof is
administered at a
dose of 8 mg once daily and everolimus is co-administered at a dose of 2.5 mg
once
daily. In yet another embodiment, lenvatinib or pharmaceutically acceptable
salt
thereof is administered at a dose of 8 mg once daily and everolimus is co-
administered
at a dose of 2.5 mg once every other day. In a different embodiment,
lenvatinib or
pharmaceutically acceptable salt thereof (e.g., lenvatinib mesylate) is
administered at a
dose of 6 mg once daily and everolimus is co-administered at a dose of 5 mg
once
daily. In one embodiment, lenvatinib or pharmaceutically acceptable salt
thereof is ad-
CA 03019682 2018-10-01
ministered at a dose of 6 mg once daily and everolimus is co-administered at a
dose of
5 mg once every other day. In another embodiment, lenvatinib or
pharmaceutically ac-
ceptable salt thereof is administered at a dose of 6 mg once daily and
everolimus is co-
administered at a dose of 2.5 mg once daily. In yet another embodiment,
lenvatinib or
pharmaceutically acceptable salt thereof is administered at a dose of 6 mg
once daily
and everolimus is co-administered at a dose of 2.5 mg once every other day.
[0107] It is recommended that the subject take lenvatinib or a
pharmaceutically acceptable
salt thereof and everolimus one time each day at about the same time, with or
without
food. In certain embodiments, the subject should not take a CYP3A4 inhibitor
and/or a
Pgp inhibitor. In certain embodiments, the subject should not take herbal
supplements
and/or eat grapefruits and/or drink grapefruit juice.
[0108] If the patient is unable to swallow the lenvatinib capsules whole,
the patient may use
a cup to measure about one tablespoon of water or apple juice into a glass and
place
the drug capsules into the liquid without breaking or crushing them. The
capsules
should be left in the liquid for at least 10 minutes and the contents then
stirred for at
least 3 minutes. The patient can then drink this mixture. After drinking, the
patient
should rinse the glass with a small amount of additional water or apple juice
and
swallow the liquid.
[0109] In certain embodiments, lenvatinib or the pharmaceutically
acceptable salt thereof
and everolimus are administered to a subject that has a RCC once daily for at
least 7
weeks, at least 14 weeks, at least 28 weeks, at least 56 weeks, at least 84
weeks, at
least 112 weeks, at least 140 weeks, at least 168 weeks, or at least 196
weeks.
[0110] Methods of Treatment to Control, Reduce, or Prevent Adverse Events
A major problem in treating a subject with a new therapy is the development of
a
treatment-emergent adverse event(s) (1bAE). A treatment-emergent adverse event
is
as any adverse event not present in the subject prior to the initiation of the
treatment, or
any adverse event already present that worsens in either intensity or
frequency
following exposure to the treatment. In certain embodiments, the adverse event
is a
persistent and intolerable adverse event.
[0111] The National Cancer Institute Common Terminology Criteria for
Adverse Events
v4.0 (CTCAE, published: May 28, 2009; v4.03: June 14, 2010) (incorporated by
reference herein in its entirety) is a descriptive terminology that can be
utilized for
adverse event reporting. The CTCAE provides a grading (severity) scale for
each
adverse event term. An Adverse Event (AE) is any unfavorable and unintended
sign
(including an abnormal laboratory finding), symptom, or disease temporally
associated
with the use of a medical treatment or procedure that may or may not be
considered
related to the medical treatment or procedure. An AE is a term that is a
unique repre-
sentation of a specific event used for medical documentation and scientific
analyses.
CA 03019682 2018-10-01
31
An AE can be graded. The CTCAE grade refers to the severity of the AE. The
CTCAE
displays Grades 1 through 5 with unique clinical descriptions of severity for
each AE
based on this guideline:
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic
observations
only; intervention not indicated.
Grade 2: Moderate; minimal, local or noninvasive intervention indicated;
limiting age-
appropriate instrumental Activities of Daily Living (ADL). [Instrumental ADL"
refer
to preparing meals, shopping for groceries or clothes, using the telephone,
managing
money, etc.]
Grade 3: Severe or medically significant but not immediately life-threatening;
hospi-
talization or prolongation of hospitalization indicated; disabling; limiting
self-care
ADL. ["Self-care ADL" refers to bathing, dressing and
undressing, feeding self, using the toilet, taking medications, and not
bedridden.]
Grade 4: Life-threatening consequences; urgent intervention indicated.
Grade 5: Death related to AR
[0112] Not all Grades are appropriate for all AEs. Therefore, some AEs are
listed in the
CTCAE with fewer than five options for Grade selection.
[0113] Combination therapy with lenvatinib or a pharmaceutically acceptable
salt thereof
can lead to treatment-emergent adverse events (see, Example 2). In certain em-
bodiments, the adverse event associated with therapy with the combination of
lenvatinib or a pharmaceutically acceptable salt thereof and everolimus is a
persistent
and intolerable AE. In certain instances, the persistent and intolerable AE is
a Grade 2
AE. In other instances, the persistent and intolerable AE is a Grade 3 AE. In
certain
embodiments, the adverse event associated with the combination therapy of
lenvatinib
or a pharmaceutically acceptable salt thereof and everolimus is a Grade 4 AE.
In yet
other instances, the persistent and intolerable AE is a Grade 4 laboratory
abnormality.
The most common adverse reactions observed in the LENVIMA(Registered
Trademark) 4.
everolimus-treated subjects were, in order of decreasing frequency, diarrhea,
decreased
appetite, fatigue, vomiting, nausea, hypertension, cough, and decreased
weight.
[0114] Diarrhea is a disorder characterized by frequent and watery bowel
movements and is
graded as follows:
Grade 1: Increase of <4 stools per day over baseline; mild increase in ostomy
output
compared to baseline
Grade 2: Increase of 4 - 6 stools per day over baseline; moderate increase in
ostomy
output compared to baseline
Grade 3: Increase of >=7 stools per day over baseline; incontinence;
hospitalization
indicated; severe increase in ostomy output compared to baseline; limiting
self-care
ADL
CA 03019682 2018-10-01
32
Grade 4: Life-threatening consequences; urgent intervention indicated
Grade 5: death
[0115] Fatigue is a disorder characterized by a state of generalized
weakness with a
pronounced inability to summon sufficient energy to accomplish daily
activities and is
graded as follows:
Grade 1: Fatigue relieved by rest
Grade 2: Fatigue not relieved by rest; limiting instrumental ADL
Grade 3: Fatigue not relieved by rest, limiting self-care ADL
Grade 4: Not available
Grade 5: Not available
[0116] Vomiting is a disorder characterized by the reflexive act of
ejecting the contents of
the stomach through the mouth, and is graded as follows:
Grade 1: 1 - 2 episodes (separated by 5 minutes) in 24 hrs
Grade 2: 3 - 5 episodes (separated by 5 minutes) in 24 hrs
Grade 3: >=6 episodes (separated by 5 minutes) in 24 hrs; tube feeding, TPN or
hos-
pitalization indicated
Grade 4: Life-threatening consequences; urgent intervention indicated
Grade 5: Death
[0117] Nausea is a disorder characterized by a queasy sensation and/or the
urge to vomit,
and is graded as follows:
Grade 1: Loss of appetite without alteration in eating habits
Grade 2: Oral intake decreased without significant weight loss, dehydration or
mal-
nutrition
Grade 3: Inadequate oral caloric or fluid intake; tube feeding, TPN, or
hospitalization
indicated
Grade 4: Not available
Grade 5: Not available
[0118] Hypertension is a disorder characterized by a pathological increase
in blood pressure;
a repeatedly elevation in the blood pressure exceeding 140 over 90 mm Hg, and
is
graded as follows:
Grade 1: Prehypertension (systolic BP 120- 139 mm Hg or diastolic BP 80- 89 mm
Hg)
Grade 2: Stage 1 hypertension (systolic BP 140 - 159 mm Hg or diastolic BP 90 -
99
mm Hg); medical intervention indicated; recurrent or persistent (>=24 hrs);
symptomatic increase by>20 mm Hg (diastolic) or to >140/90 mm Hg if previously
WNL; monotherapy indicated Pediatric: recurrent or persistent (>=24 hrs) BP
>ULN;
monotherapy indicated
Grade 3: Stage 2 hypertension (systolic BP >=160 mm Hg or diastolic BP >=100
mm
CA 03019682 2018-10-01
33
Hg); medical intervention indicated; more than one drug or more intensive
therapy
than previously used indicated Pediatric: Same as adult
Grade 4: Life-threatening consequences (e.g., malignant hypertension,
transient or
permanent neurologic deficit, hypertensive crisis); urgent intervention
indicated
Pediatric: Same as adult
Grade 5: Death
[0119] Cough is a disorder characterized by sudden, often repetitive,
spasmodic contraction
of the thoracic cavity, resulting in violent release of air from the lungs and
usually ac-
companied by a distinctive sound, and is graded as follows:
Grade 1: Mild symptoms; nonprescription intervention indicated
Grade 2: Moderate symptoms, medical intervention indicated; limiting
instrumental
ADL
Grade 3: Severe symptoms; limiting self-care ADL
Grade 4: Not available
Grade 5: Not available
[0120] Decreased appetite is a disorder characterized by a loss of
appetite, and is graded as
follows:
Grade 1: Loss of appetite without alteration in eating habits
Grade 2: Oral intake altered without significant weight loss or malnutrition;
oral nu-
tritional supplements indicated
Grade 3: Associated with significant weight loss or malnutrition (e.g.,
inadequate
oral caloric and/or fluid intake); tube feeding or TPN indicated
Grade 4: Life-threatening consequences; urgent intervention indicated
Grade 5: Death
[0121] Decreased weight is a finding characterized by a decrease in overall
body weight; for
pediatrics, less than the baseline growth curve, and is graded as follows:
Grade 1: Weight loss 5 to <10% from baseline; intervention not indicated
Grade 2: 10- <20% from baseline; nutritional support indicated
Grade 3: >=20% from baseline; tube feeding or TPN indicated
Grade 4: Not available
Grade 5: Not available
[0122] The most common serious adverse reactions in the
LENVIMA(RegisteredThdemark)
everolimus-treated group were anemia, dehydration, acute renal failure,
diarrhea, and
thrombocytopenia.
[0123] Anemia is a disorder characterized by a reduction in the amount of
hemoglobin in
100 ml of blood. Signs and symptoms of anemia may include pallor of the skin
and
mucous membranes, shortness of breath, palpitations of the heart, soft
systolic
murmurs, lethargy, and fatigability, and is graded as follows:
CA 03019682 2018-10-01
34
Grade 1: Hemoglobin (Hgb) <LLN -10.0 g/dL; <LLN - 6.2 mmol/L; <LLN - 100 g/L
Grade 2: Hgb <10.0 - 8.0 g/dL; <6.2 -4.9 mmol/L; <100 - 80gfL
Grade 3: Hgb <8.0 g/dL; <4.9 mmol/L; <80 g/L; transfusion indicated
Grade 4: Life-threatening consequences; urgent intervention indicated
Grade 5: Death
[0124] Dehydration is a disorder characterized by excessive loss of water
from the body. It
is usually caused by severe diarrhea, vomiting or diaphoresis, and is graded
as follows:
Grade 1: Increased oral fluids indicated; dry mucous membranes; diminished
skin
turgor
Grade 2: IV fluids indicated <24 hrs
Grade 3: IV fluids or hospitalization indicated
Grade 4: Life-threatening consequences; urgent intervention indicated
Grade 5: Death
[0125] Acute renal failure is a disorder characterized by the acute loss of
renal function and
is traditionally classified as pre-renal (low blood flow into kidney), renal
(kidney
damage) and postrenal causes (ureteral or bladder outflow obstruction) and is
graded as
follows:
Grade 1: Creatinine level increase of >0.3 mg/dL; creatinine 1.5 -2.0 x above
baseline
Grade 2: Creatinine 2 - 3 x above baseline
Grade 3: Creatinine >3 x baseline or >4.0 mg/dL; hospitalization indicated
Grade 4: Life-threatening consequences; urgent intervention indicated
Grade 5: Death
[0126] Thrombocytopenia is a finding based on laboratory test results that
indicate a
decrease in number of platelets in a blood specimen, and is graded as follows:
Grade 1: <LLN - 75,000/mm3; <LLN - 75.0 x 109 /L
Grade 2: <75,000 - 50,000/mm3; <75.0 - 50.0 x 109 /L
Grade 3: <50,000 - 25,000/mm3; <50.0 - 25.0 x 109 /L
Grade 4: <25,000/mm3; <25.0 x 109 /L
Grade 5: Not available
[0127] This disclosure provides dose modifications for lenvatinib or a
pharmaceutically ac-
ceptable salt thereof and/or everolimus upon the occurrence of a treatment-
emergent
adverse event(s) during the course of the combination therapy. In certain
embodiments,
the subject that has a RCC is administered a first dosage regimen comprising
lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 18
mg/day and
everolimus at a dose of 5 mg/day. In other embodiments, the subject that has a
RCC is
administered a first dosage regimen comprising lenvatinib or a
pharmaceutically ac-
ceptable salt thereof at a dose of 14 mg/day and everolimus at a dose of 5
mg/day. In
CA 03019682 2018-10-01
some cases, the subject may develop a Grade 1 or tolerable Grade 2 adverse
reaction
after being administered the first dosage regimen. hi such instances,
treatment of the
subject can continue without any changes to the first dosage regimen.
Following or
during treatment period with the first dosage regimen comprising lenvatinib or
a phar-
maceutically acceptable salt thereof at a dose of 14 mg/day and everolimus at
a dose of
5 mg/day, if the human subject does not develop an intolerable Grade 2 or
Grade 3
adverse reaction or Grade 4 laboratory abnormality, the dosage regimen can be
up-
titrated (e.g., comprising Ienvatinib or a pharmaceutically acceptable salt
thereof at a
dose of18 mg/day and everolimus at a dose of 5 mg/day).
[0128] In some embodiments, the subject may develop a persistent and
intolerable Grade 2
or Grade 3 adverse reaction during the period of treatment with the first
dosage
regimen that is related to one or both compounds of the combination therapy.
In certain
instances, the subject develops a persistent and intolerable Grade 2 or Grade
3 adverse
reaction within 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks,
8
weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16
weeks, 17 weeks, 18 weeks, 19 weeks, or 20 weeks after the administration of
the first
dosage regimen. In one embodiment, the subject develops a persistent and
intolerable
Grade 2 or Grade 3 adverse reaction within 12 weeks after the administration
of the
first dosage regimen. In another embodiment, the subject develops a persistent
and in-
tolerable Grade 2 or Grade 3 adverse reaction within 16 weeks after the
administration
of the first dosage regimen. In certain instances, the AE is diarrhea. In
other instances,
the AE is vomiting. In yet other instances, the AE is nausea. In still other
instances, the
AE is proteinuria. In other instances, the AE is decreased appetite. In some
instances,
the AE is fatigue. In some instances, the AE is hypertension. In some
instances, the AE
is cough. In other instances, the AE is decreased weight. In certain
instances, the Grade
2 or Grade 3 adverse reaction is Grade 3 hypertension, Grade 2 hypertension,
Grade 3
cardiac dysfunction, Grade 2 cardiac dysfunction, Grade 3 arterial
thromboembolic
event, Grade 2 arterial thromboembolic event, Grade 3 proteinuria, Grade 2 pro-
teinuria, Grade 3 renal failure or impairment, Grade 2 renal failure or
impairment,
Grade 3 diarrhea, Grade 2 diarrhea, Grade 3 gastrointestinal perforation or
fistula,
Grade 2 gastrointestinal perforation or fistula, Grade 3 vomiting, Grade 2
vomiting,
Grade 3 decreased appetite, Grade 2 decreased appetite, Grade 3 fatigue, Grade
2
fatigue, Grade 3 nausea, Grade 2 nausea, Grade 3 cough, Grade 2 cough, Grade 3
decreased weight, Grade 2 decreased weight, Grade 3 dehydration, Grade 2 de-
hydration, Grade 3 thrombocytopenia, Grade 2 thrombocytopenia, Grade 3 anemia,
Grade 2 anemia, Grade 3 acute renal failure, Grade 2 acute renal failure,
Grade 3 pro-
teinuria, Grade 2 proteinuria, Grade 3 QT/QTe interval prolongation, Grade 2
QT/QTe
interval prolongation, Grade 3 reversible posterior leukoencephalopathy
syndrome
CA 03019682 2018-10-01
36
(RPLS), Grade 2 RPLS, Grade 3 hemorrhagic events, Grade 2 hemorrhagic events,
Grade 3 hyperthyroidism, or Grade 2 hyperthyroidism. In some instance, the
adverse
event may be a Grade 4 laboratory abnormality (e.g., increased lipase,
hypertriglyc-
eridemia, hypophosphatemia, high cholesterol, hyponatremia, hypokalemia, hy-
perkalemia, hypocalcemia, hyperglycemia, increased aspartate aminotransferase,
increased alanine aminotransferase, or increased alkaline phosphatase). In
certain
instances, the Grade 4 laboratory abnormality is Grade 4 increase in aspartate
amino-
transferase, Grade 4 increase in alanine arninotransferase, Grade 4 increase
in alkaline
phosphatase, Grade 4 hyperkalemia, Grade 4 hypokalernia, Grade 4 hyponatremia,
Grade 4 hypocalcemia, Grade 4 hypophosphatemia, Grade 4 hyperglycemia, Grade 4
hypertriglyceridemia, Grade 4 increase in cholesterol, Grade 4 increase in
lipase,
Grade 4 decrease in hemoglobin, Grade 4 decrease in platelet count, or Grade 4
decrease in lymphocyte count. In certain instances, the subject develops a
Grade 4 AE.
In some cases, the Grade 4 AE is renal failure or renal impairment. In some
cases, the
Grade 4 AE is hepatotoxicity.
[01291 If the subject develops a persistent and intolerable Grade 2 or
Grade 3 adverse
reaction, or a Grade 4 laboratory abnormality after being administered the
first dosage
regimen (i.e., lenvatinib or a pharmaceutically acceptable salt thereof at a
dose of 18
mg/day and everolimus at a dose of 5 mg/day), the healthcare provider can
terminate
the first dosage regimen and administer to the subject a second dosage regimen
comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose
of 14 mg/
day. Similarly, if this occurs when the first dosage regimen comprises
lenvatinib or a
pharmaceutically acceptable salt thereof at a dose of 14 mg/day, the
healthcare
provider can terminate the first dosage regimen and administer to the subject
a second
dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt
thereof at
a dose of 10 mg/day. If the health care provider believes that the adverse
reaction to
the combination therapy of the first dosage regimen is unrelated to everolimus
admin-
istration, the second dosage regimen can include everolimus at a dose of 5
mg/day (i.e.,
lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 14
mg/day and
everolimus at a dose of 5 mg/day). If, however, the health care provider
believes that
the adverse reaction to the lenvatinib + everolimus combination therapy of the
first
dosage regimen is probably or possibly related to everolimus administration,
the
healthcare provider can reduce the dosage of everolimus that is administered
along
with the lenvatinib or a pharmaceutically acceptable salt thereof in the
second dosage
regimen. For example, if the health care provider believes that the adverse
reaction to
the lenvatinib + everolimus combination therapy of the first dosage regimen is
probably or possibly related to everolimus administration, the second dosage
regimen
may comprise, e.g., lenvatinib or a pharmaceutically acceptable salt thereof
at a dose
CA 03019682 2018-10-01
37
of 14 mg/day and everolimus at a dose of 5 mg every other day; lenvatinib or a
phar-
maceutically acceptable salt thereof at a dose of 14 mg/day and everolimus at
a dose of
2.5 mg/day; or lenvatinib or a pharmaceutically acceptable salt thereof at a
dose of 14
mg/day and everolimus at a dose of 2.5 mg every other day. In certain
instances, the
second dosage regimen is administered after interruption of the first dosage
regimen
and after the adverse reaction observed after the first dosage regimen is
resolved to
Grade 0-1 or baseline (or Grade 0-1 or tolerable Grade 2). In certain
instances, the
second dosage regimen is administered after interruption of the first dosage
regimen
and after the adverse reaction observed after the first dosage regimen is
resolved to less
than or equal to Grade 2. In some instances, the first dosage regimen is
terminated only
after commencement of medical management of the persistent and intolerable
Grade 2
or Grade 3 adverse reaction, or a Grade 4 laboratory abnormality. In specific
em-
bodiments, the persistent and intolerable Grade 2 or Grade 3 adverse reaction
is
diarrhea, vomiting, nausea, or proteinuria. If the persistent and intolerable
Grade 2 or
Grade 3 adverse reaction is proteinuria, in one embodiment, the therapy with
lenvatinib
or a pharmaceutically acceptable salt thereof is withheld for >=.= 2 grams of
proteinuria!
24 hours, and the treatment with lenvatinib or a pharmaceutically acceptable
salt
thereof is resumed at a lower dose (e.g., 14 mg/day) when proteinuria is <2
gm/24
hours; however, treatment with lenvatinib or a pharmaceutically acceptable
salt thereof
is discontinued if the subject develops nephrotic syndrome. If the persistent
and in-
tolerable Grade 3 adverse reaction is hypertension, in one embodiment, the
subject is
provided antihypertensive therapy and treatment with lenvatinib or a
pharmaceutically
acceptable salt thereof is resumed at a lower dose (e.g., 14 mg/day) when
hypertension
is controlled at less than or equal to Grade 2; however, therapy with
lenvatinib or a
pharmaceutically acceptable salt thereof is discontinued for life-threatening
hy-
pertension. If the persistent and intolerable Grade 3 adverse reaction is
cardiac dys-
function or hemorrhage, in one embodiment, therapy with lenvatinib or a pharma-
ceutically acceptable salt thereof is withheld until improvement to Grade 0 or
1 or
baseline (or Grade 0-1 or tolerable Grade 2) and then the subject is
administered
lenvatinib or a pharmaceutically acceptable salt thereof at a lower dose
(e.g., 14 mg/
day); however, therapy with lenvatinib or a pharmaceutically acceptable salt
thereof is
discontinued if the cardiac dysfunction or hemorrhage is severe and/or
persistent. If the
adverse reaction is an arterial thrombotic event, therapy with lenvatinib or a
pharma-
ceutically acceptable salt thereof is discontinued. If the subject develops
Grade 3 or
Grade 4 renal failure/impairment or hepatotoxicity, in one embodiment,
treatment with
lenvatinib or a pharmaceutically acceptable salt thereof is withheld until the
adverse
reaction is resolved to Grade 0 to 1 or baseline (or Grade 0-1 or tolerable
Grade 2) and
resumed at a lower dose (e.g., 14 mg/day); however, therapy with lenvatinib or
a phar-
CA 03019682 2018-10-01
38
rnaceutically acceptable salt thereof is discontinued if the renal
failure/impairment or
hepatotoxicity is severe (e.g., hepatic failure) and/or persistent If the
adverse reaction
is a gastrointestinal perforation or life-threatening fistula formation,
therapy with
lenvatinib or a pharmaceutically acceptable salt thereof is discontinued. If
the adverse
reaction is a Grade 3 or greater QT interval prolongation, therapy with
lenvatinib or a
pharmaceutically acceptable salt thereof is discontinued and therapy can be
resumed at
a lower dose (e.g., 14 mg/day) when QT prolongation resolves to Grade 0 or 1
or
baseline (or Grade 0-1 or tolerable Grade 2). If the adverse reaction is RPLS,
therapy
with lenvatinib or a pharmaceutically acceptable salt thereof is discontinued
until the
adverse reaction is fully resolved; upon resolution, therapy with lenvatinib
or a phar-
maceutically acceptable salt thereof can be resumed at a lower dose (e.g., 14
mg/day),
or discontinued if neurologic symptoms are severe and/or persistent.
[01301 In some cases, even after administration of the second dosage
regimen, a subject may
develop an adverse reaction. In certain instances, the subject develops a
persistent and
intolerable Grade 2 or Grade 3 adverse reaction within 1 week, 2 weeks, 3
weeks, 4
weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12
weeks after the administration of the second dosage regimen. The adverse
reaction
after the second dosage regimen may be the same as, or different from, the
adverse
reaction after the first dosage regimen. The adverse reaction after the second
dosage
regimen may be a persistent and intolerable Grade 2 or Grade 3 adverse
reaction. In
certain instances, the AE is diarrhea. In other instances, the AE is vomiting.
In yet
other instances, the AE is nausea. In still other instances, the AE is
proteinuria. In other
instances, the AE is decreased appetite. In some instances, the AE is fatigue.
In some
instances, the AE is hypertension. In some instances, the AE is cough. In
other
instances, the AE is decreased weight. In some embodiments, the adverse event
may be
a Grade 4 laboratory abnormality (e.g., increased lipase,
hypertrig,lyceridernia, hy-
pophosphatetnia, high cholesterol, hyponatremia, hypokalemia, hyperkalemia,
hypocalcemia, hyperglycemia, increased aspartate aminotransferase, increased
alanine
aminotransferase, or increased alkaline phosphatase). In certain instances,
the subject
develops a Grade 4 AE In some cases, the Grade 4 AE is renal failure or renal
im-
pairment. In some cases, the Grade 4 AE is hepatotoxicity. If the subject
develops a
persistent and intolerable Grade 2 or Grade 3 adverse reaction, or a Grade 4
laboratory
abnormality after being administered the second dosage regimen (e.g.,
lenvatinib or a
pharmaceutically acceptable salt thereof at a dose of 14 mg/day and everolimus
at a
dose of 5 mg/day), the healthcare provider can terminate the second dosage
regimen
and administer to the subject a third dosage regimen comprising lenvatinib or
a phar-
maceutically acceptable salt thereof at a dose of 10 mg/day. Similarly, if
this occurs
when the second dosage regimen comprises lenvatinib or a pharmaceutically ac-
CA 03019682 2018-10-01
39
ceptable salt thereof at a dose of 10 mg/day, the healthcare provider can
terminate the
second dosage regimen and administer to the subject a third dosage regimen
comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose
of 8 mg/
day. If the health care provider believes that the adverse reaction to the
second dosage
regimen is unrelated to everolimus administration, the third dosage regimen
can
include everolimus at a dose of 5 mg/day (i.e., lenvatinib or a
pharmaceutically ac-
ceptable salt thereof at a dose of 10 mg/day and everolimus at a dose of 5
mg/day). If,
- however, the health care provider believes that the adverse reaction to
the lenvatinib +
everolimus combination therapy of the second dosage regimen is probably or
possibly
related to everolimus administration, the healthcare provider can reduce the
dosage of
everolimus that is administered along with lenvatinib or a pharmaceutically
acceptable
salt thereof in the third dosage regimen. For example, if the health care
provider
believes that the adverse reaction to the second dosage regimen is probably or
possibly
related to everolimus administration, the third dosage regimen may comprise,
e.g.,
lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 10
mg/day and
everolimus at a dose of 5 mg every other day; lenvatinib or a pharmaceutically
ac-
ceptable salt thereof at a dose of 10 mg/day and everolimus at a dose of 2.5
mg/day; or
lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 10
mg/day and
everolimus at a dose of 2.5 mg every other day. In certain instances, the
third dosage
regimen is administered after termination of the second dosage regimen and
after the
adverse reaction observed after the second dosage regimen is resolved to Grade
0-1 or
baseline (or Grade 0-1 or tolerable Grade 2). In some instances, the second
dosage
regimen is terminated only after commencement of medical management of the
persistent and intolerable Grade 2 or Grade 3 adverse reaction, or a Grade 4
laboratory
abnormality. In specific embodiments, the persistent and intolerable Grade 2
or Grade
3 adverse reaction is diarrhea, vomiting, nausea, or proteinuria.
[0131] In certain embodiments, even after administration of the third
dosage regimen, a
subject may develop an adverse reaction. In certain instances, the subject
develops a
persistent and intolerable Grade 2 or Grade 3 adverse reaction within 1 week,
2 weeks,
3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11
weeks,
or 12 weeks after the administration of the third dosage regimen. The adverse
reaction
after the third dosage regimen may be the same as, or different from, the
adverse
reaction after the second and/or first dosage regimen. The adverse reaction
after the
third dosage regimen may be a persistent and intolerable Grade 2 or Grade 3
adverse
reaction. In certain instances, the AE is diarrhea. In other instances, the AE
is
vomiting. In yet other instances, the AE is nausea. In still other instances,
the AE is
proteinuria. In other instances, the AE is decreased appetite. In some
instances, the AE
is fatigue. In some instances, the AE is hypertension. In some instances, the
AE is
CA 03019682 2018-10-01
cough. In other instances, the AE is decreased weight. In some embodiments,
the
adverse event may be a Grade 4 laboratory abnormality (e.g., increased lipase,
hyper-
triglyceridemia, hypophosphatemia, high cholesterol, hyponatremia,
hypokaletnia, hy-
perkalemia, hypocaleemia, hyperglycemia, increased aspartate
arninotransferase,
increased alanine arninotransferase, or increased alkaline phosphatase). In
certain
instances, the subject develops a Grade 4 AR In some cases, the Grade 4 AE is
renal
failure or renal impairment. In some cases, the Grade 4 AE is hepatotoxicity.
If the
subject develops a persistent and intolerable Grade 2 or Grade 3 adverse
reaction, or a
Grade 4 laboratory abnormality, after being administered the third dosage
regimen
(e.g., lenvatinib or a pharmaceutically acceptable salt thereof at a dose of
10 mg/day
and everolimus at a dose of 5 mg/day), the healthcare provider can terminate
the third
dosage regimen and administer to the subject a fourth dosage regimen
comprising
lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8
mg/day.
Similarly, if this occurs when the third dosage regimen comprises lenvatinib
or a phar-
maceutically acceptable salt thereof at a dose of 8 mg/day, the healthcare
provider can
terminate the third dosage regimen and administer to the subject a fourth
dosage
regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at
a dose
of 4 mg/day. If the health care provider believes that the adverse reaction to
the third
dosage regimen is unrelated to everolimus administration, the fourth dosage
regimen
can include everolimus at a dose of 5 mg/day (i.e., lenvatinib or a
pharmaceutically ac-
ceptable salt thereof at a dose of 8 mg/day and everolimus at a dose of 5
mg/day). If,
however, the health care provider believes that the adverse reaction to the
lenvatinib
everolimus combination therapy is probably or possibly related to everolimus
admin-
istration, the healthcare provider can reduce the dosage of everolimus that is
ad-
ministered along with the 8 mg/day of lenvatinib or a pharmaceutically
acceptable salt
thereof in the fourth dosage regimen. For example, if the health care provider
believes
that the adverse reaction to the third dosage regimen is probably or possibly
related to
everolimus administration, the fourth dosage regimen may comprise, e.g.,
lenvatinib or
a pharmaceutically acceptable salt thereof at a dose of 8 mg/day and
everolimus at a
dose of 5 mg every other day; lenvatinib or a pharmaceutically acceptable salt
thereof
at a dose of 8 mg/day and everolimus at a dose of 2.5 mg/day; or lenvatinib or
a phar-
maceutically acceptable salt thereof at a dose of 8 mg/day and everolimus at a
dose of
2.5 mg every other day. In certain instances, the fourth dosage regimen is
administered
after interruption of the third dosage regimen and after the adverse reaction
observed
after the third dosage regimen is resolved to Grade 0-1 or baseline (or Grade
0-1 or
tolerable Grade 2). In some instances, the third dosage regimen is terminated
only after
commencement of medical management of the persistent and intolerable Grade 2
or
Grade 3 adverse reaction, or a Grade 4 laboratory abnormality. In specific em-
CA 03019682 2018-10-01
41
bodiments, the persistent and intolerable Grade 2 or Grade 3 adverse reaction
is
diarrhea, vomiting, nausea, or proteinuria.
[0132] In some instances, the subject that has a RCC may have severe renal
impairment
(creatinine clearance [CLcr] less than 30 mL/min calculated by the Cockcroft-
Gault
equation) or severe hepatic impairment (Child-Pugh C). For such subjects, the
first
dose regimen can comprise lenvatinib or a pharmaceutically acceptable salt
thereof at a
dose of 14 mg/day and everolimus at a dose of 2.5 mg/day. If the subject
develops
adverse reactions during the course of treatment with the first dose regimen,
the admin-
istration of the first dosage regimen may be terminated and a lower dosage
regimen ad-
ministered. For example, the subject may be administered a second dosage
regimen
comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose
of 10 mg/
day (and optionally everolimus at a dose of 2.5 mg/day or everolimus at a dose
of 2.5
mg every other day). If the subject develops adverse reactions during the
course of
treatment with the second dose regimen, the administration of the second
dosage
regimen may be terminated and a lower dosage regimen administered. For
example,
the subject may be administered a third dosage regimen comprising lenvatinib
or a
pharmaceutically acceptable salt thereof at a dose of 8 mg/day (and optionally
everolimus at a dose of 2.5 mg/day or everolimus at a dose of 2.5 mg every
other day).
If the subject develops adverse reactions during the course of treatment with
the third
dose regimen, the administration of the third dosage regimen may be terminated
and a
lower dosage regimen administered. For example, the subject may be
administered a
fourth dosage regimen comprising lenvatinib or a pharmaceutically acceptable
salt
thereof at a dose of 6 mg/day (and optionally everolimus at a dose of 2.5
mg/day or
everolimus at a dose of 2.5 mg every other day).
[0133] In certain embodiments for treating a subject that has a RCC and
also suffers from
either severe renal impairment or severe hepatic impairment, the first dose
regimen
comprises lenvatinib or a pharmaceutically acceptable salt thereof at a dose
of 10 mg/
day and everolimus at a dose of 2.5 mg/day. If the subject develops adverse
reactions
during the course of treatment with the first dose regimen, the administration
of the
first dosage regimen may be terminated and a lower dosage regimen
administered. For
example, the subject may be administered a second dosage regimen comprising
lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day
(and op-
tionally everolimus at a dose of 2.5 mg/day or everolimus at a dose of 2.5 mg
every
other day). If the subject develops adverse reactions during the course of
treatment
with the second dose regimen, the administration of the second dosage regimen
may be
terminated and a lower dosage regimen administered. For example, the subject
may be
administered a third dosage regimen comprising lenvatinib or a
pharmaceutically ac-
ceptable salt thereof at a dose of 6 mg/day (and optionally everolimus at a
dose of 2.5
CA 03019682 2018-10-01
42
mg/day or everolimus at a dose of 2.5 mg every other day). If the subject
develops
adverse reactions during the course of treatment with the third dose regimen,
the ad-
ministration of the third dosage regimen may be terminated and a lower dosage
regimen administered. For example, the subject may be administered a fourth
dosage
regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at
a dose
of 5 mg/day (and optionally everolimus at a dose of 2.5 mg/day or everolimus
at a dose
of 2.5 mg every other day). In certain instance, if Grade 3 toxicity is
observed, admin-
istration of everolimus can be terminated.
101341 The following are examples of the practice of the invention. They
are not to be
construed as limiting the scope of the invention in any way.
[0135] Examples
Example 1: Determination of Safety and Efficacy of Lenvatinib Therapies
A multicenter, randomized, open-label, trial was conducted to determine the
safety
and efficacy of lenvatinib administered alone or in combination with
everolimus in
subjects with unresectable advanced or metastatic renal cell carcinoma (RCC).
The
trial consisted of a Phase lb dose finding and a Phase 2 portion. The Phase 2
portion
enrolled a total of 153 patients with unresectable advanced or metastatic RCC
following one prior VEGF-targeted treatment. Patients were required, inter
alia, to
have histological confirmation of predominant clear cell RCC, radiographic
evidence
of disease progression according to Response Evaluation Criteria in Solid
Tumors
Version 1.1 (RECIST), one prior VEGF-targeted therapy, and Eastern Cooperative
Oncology Group (ECOG) Performance Status of 0 or 1.
[0136] Patients were randomly allocated to one of 3 arms: (i)
LENVIMA(Registered Trademark)
(mesylate salt of lenvatinib) 18 mg + everolimus 5 mg, (ii) LENVIMA(Registered
Trademark)
24 mg, or (iii) everolimus 10 mg, using a 1:1:1 ratio. Patients were
stratified by
hemoglobin level (<=13 g/dL vs. >13 g/dL for males and <=11.5 g/dL vs >11.5
g/dL
for females) and corrected serum calcium (>=10 mg/dL vs. <10 mg/dL).
[0137] The primary efficacy outcome measure, based on investigator assessed
tumor
response, was progression-free survival (PFS) of the LENVIMA(Registered
Trademark) plus
everolimus arm vs. the everolimus arm and of the LENVIIVIA(Registered
Trademark) arm vs. the
everolimus arm. Other efficacy outcome measures included investigator-assessed
overall survival (OS) and objective response rate (ORE.).
[0138] Of the 153 patients randomly allocated, 73% were male, the median
age was 61
years, 36% were older than 65 years, and 97% were white. Metastases were
present in
95% of the patients and unresectable advanced disease was present in 5%. All
patients
had a baseline Eastern Cooperative Oncology Group (ECOG) performance status
(PS)
of either 0 (55%) or 1 (45%) with similar distribution across the 3 treatment
arms.
Memorial Sloan Kettering Cancer Center (MSKCC) poor risk was observed in 39%
of
CA 03019682 2018-10-01
43
patients in the LENVIMA(Regrarered Trademark) + everolimus arm, 44% in the
LENVIMA
(Registered Trademark) arm, and 38% in the everolimus arm. The median time
from diagnosis to
first dose was 32 months in the LENVIMA( Rte'teteA Tilden.rk) + everolimus-
treatment arm,
33 months in the LENVIMA(Registered Trademark) arm, and 26 months in the
everolimus arm.
[01391 Tumor assessments were evaluated according to RECIST. The
LENVIMA(Registerm
Trademark) + everolimus arm showed a statistically significant and clinically
meaningful
improvement in PFS compared with the everolimus arm (see, Table 1 and Fig. 1).
The
LENVIMA arm also showed an improvement in PFS compared with the everolimus
arm (see, Table 1 and Fig. 1). Overall survival was longer in the LENVIMA +
everolimus arm; a trend that was maintained through the cutoff for the updated
OS
analysis (see, Table 1 and Figs. 2 and 3).
[0140]
=
CA 03019682 2018-10-01
44
[Table I]
Table 1: Efficacy Results in Renal Cell Carcinoma (Investigator Assessment)
LENVIMe LENVIMA4) Everolimus
18mg + 24mg 10mg
Everolimus 5mg
(N=51) (N=52) (N=50)
Progression-Free Survival (PFS)11
Median PFS in months (95% CI) 14.6 (5.9, 20.1) 7.4 (5.6, 10.2) 5.5
(3.5, 7.1)
Hazard Ratio (95% CI)b 0.40 (0.24, 0.68)
LENVIMA Everolimus vs
Everolimus
P Value 0.0005
LENVIMA Everolimus vs
Everolimus
Overall Survival (OS)
Number of deaths (%) 19 (37) 26 (50) 26 (52)
= Median OS in months (95% CI) 25.5
(20.8,25.5) 18.4 (13.3, NE) 17.5 (11.8, NE)
Hazard Ratio (95% Cl) 0.55 (0.30, 1.01)
LENVIMA Everolimus vs
Everolimus
P Valueb 0.0623 =
LENVIMe + Everolimus vs
Everolimus
Overall Survival (updated analysis)C
Number of deaths, n (%) 32 (63) 34 (65) 37 (74)
Median OS in months (95% CI) 25.5 (16.4,32.1) 19.1 (13.6, 26.2) 15.4 (11.8,
20.6)
Hazard Ratio (95% Cl) 0.59 (0.36, 0.97)
LENV1MA Everolimus vs
Everolimus
Objective Response Rate
Number of complete responses (%) 1 (2) 0 0
Number of partial responses (%) 21(41) 14(27) 3 (6)
Number of stable disease (%) 21(41) 27 (52) 31(62)
Number of progressive disease (%) 2 (4) 3 (6) 121,24)
Duration of response, months, 13.0 (3.7, NE) 7.5 (3.8, NE) 8.5
(7.5, 9.4)
median (95% Cl)
Tumor assessment wan based oft REC1ST 1.1 criteria. Data cutoff date Jane 13,
2014
Percentages are based on the Mai number of subjects in the Full Analysis Set
within relevant treatment group.
Cl confidence interval, NE= not estimable
a Point estimates are based on Kaplan-Meier method and 95% CLs are based on
the Greenwood formula using log-log transformation.
Is Stratified harard ratio is based on a stratified COX regression model
including treatment as a covariate factor and hemoglobin and
corrected storm calcium as strata. The Mon method was used Er correction for
tied events.
c Data cutoff date et July 31,2015
[0141] The treatment effect of LENVIMA(RegimeredTrad'k) everolimus on PFS
and Overall
Response Rate (ORE.) was also supported by a retrospective independent blinded
review of scans. The LENVIMA(Regis tered TrRdem ark) everolimus arm showed a
statistically
significant and clinically meaningful improvement in PFS (Hazard ratio
[HR]=0.50,
[95% CI: 0.26, 0.79], P=0.003) compared with the everolimus arm. Results for
ORR
were consistent with that of the investigators' assessments, 35.3% in the
LENVIIVIA
(Registered Trademark) everolimus arm, with 1 complete response and 17
partial responses; no
CA 03019682 2018-10-01
subject had an objective response in the everolimus arm (P value <0.0001) in
favor of
the LENVIMA(Registered Trademark) everolimus arm.
[0142] Example 2: Adverse Reactions in Trial Examining Lenvatinib Therapies
for RCC
The safety data described below are derived from the trial described in
Example 1,
which randomized (1:1:1) patients with unresectable advanced or metastatic
renal cell
carcinoma (RCC) to LENVIMA(Registered Trademark) 18 mg + everolimus 5 mg
(n=51),
LENVEVIA(Registered Trademark) 24 mg (n=52), or everolimus 10 mg (n=50) once
daily. The
median treatment duration was 7.6 months for LENVIMA(Registered Trademark)
everolimus,
7.4 months for LENVIMA(Reg4tered Trademark) and 4.1 months for everolimus.
Among 51
patients who received LENVIMA(Registered Trademark) everolimus in this trial,
the median
age was 61 years, 69% were men, and 98% were white.
[0143] In this trial, the most common adverse reactions observed in the
LENVIMA(Rnist'red
Trademark) + everolimus-treated group (greater than or equal to 30%) were, in
order of de-
creasing frequency, diarrhea, decreased appetite, fatigue, vomiting, nausea,
hy-
pertension, cough, and decreased weight. The most common serious adverse
reactions
(at least 5%) were anemia 4 (8%), dehydration 4 (8%), acute renal failure 3
(6%),
diarrhea 3 (6%), and thrombocytopenia 3 (6%).
[0144] Adverse reactions led to dose reductions or interruption in 88% of
patients receiving
LENVIMA(Regieered Trademark) + everolimus, 79% in patients receiving
LENVIMA(Registered
Trademark), and 54% in patients receiving everolimus. Of the 44
LENVIMA(Registered Trademark)
+ everolimus combination therapy patients who dose was reduced or interrupted
because of an adverse event, most of them (31) did not have to discontinue
entirely for
that adverse event. 13 (26%) patients discontinued treatment in the
LENVINIA(R.gislered
Trademark) + everolimus-treated group, 16 (31%) patients discontinued
treatment in the
LENVIMA(Registered Trademark)...treated group, and 6 (12%) patients
discontinued treatment
in the everolimus-treated group for adverse reactions. The most common adverse
reactions (at least 5%) resulting in dose reductions in the LENVIMA(Registered
Trademark) 4.
everolimus-treated group were diarrhea 12 (24%), vomiting 4 (8%), nausea 3
(6%),
and proteinuria 3 (6%).Table 2 presents the percentage of patients in the
trial expe-
riencing adverse reactions with a frequency of at least 10%.
[0145]
CA 03019682 2018-10-01
46
[Table 21
Table 2: Adverse Reactions with Frequency of Greater than 10% for All-Grades
or
Greater than 3% for Grade 3 and 4
LENVIMAdd 24ing Everolimas thing
LENVIMe 18ing
+
Everolimus 5mg
(N=51) (N=52) (N=50)
All Grades All Grades All Grades
System Organ Class Grades 3-4 Grades 3-4 Grades 3-4
Preferred Term (%) (A) (%) (V0) (%) e/o I
Gastrointestinal Disorders
Constipation 12 0 37 0 18 0
Diarrhea 84 20 71 12 34 2
Dyspepsia 11 0 12 2 12 0
Gastrointestinal disorders and
Abdominal pain' 39 4 33 4 8 0
Nausea 43 6 62 8 16 0
Oral inflammationb 39 0 27 2 50 4
Oral pain 18 0 14 0 4 0
_
Vomiting 47 8 39 4 12 0
General Disorders and Administration Site Conditions _
Fatigued 63 16 52 10 38 /
Peripheral edema 29 0 17 0 18 0
Pyrexia 22 2 10 0 10 2
Infections and Infestations
Dental and oral infections' 14 0 6 2 0 0
Metabolism and Nutrition Disorders
Decreased appetite 53 6 58 4 18 0
Decreased weight 31 2 50 . 6 8 0 ,
Dehydration 10 6 2 0 2 0
Musculoskeletal and Connective Tissue Disorders
Arihralgia/ niyalgiar 53 4 56 4 32 0
Musetiloskeletal chest pain 18 2 15 4 4 0
Nervous System Disorders
Headache 18 2 _ 27 6 1 10 2
Psychiatric Disorders
Confusional state 4 4 4 2 0 0
Insomnia 18 2 15 0 2 0
Renal and Urinary Disorders
Proteinuria /4 4 31 19 ' 14 2
Renal failure events g 6 6 10 6 2 2
CA 03019682 2018-10-01
47
[Table 3]
Table 2 (cont.): Adverse Reactions with Frequency of Greater than 10% for All-
Grades
or Greater than 3% for Grade 3 and 4
LENVIMA'9 24mg Everolimus 10mg
LENV1Me 18mg
Everolimus 5mg
(N=51) (N-52) (N-750)
All Grades All Grades All Grades
System Organ Class Grades 3-4 Grades 3-4 Grades 3-4
Preferred Term (%) (/o) (%) (%) (4/0) (%)
Respiratory, Thoracic and Mediastinal Disorders
Cough 39 0 17 2 30 0
Dysphonia 20 0 37 0 4 0
Dy spneah 29 2 25 2 28 8
Epistaxis 18 0 8 0 24 0
Skin and Subcutaneous Tissue Disorders
Pruritus 14 0 6 0 14 0
Rash' 22 0 15 0 30 0
Vascular Disorders
Hypertension 43 14 48 17 1 10 2
a Includes abdominal discomfort, abdominal pain, lower abdominal
pain, upper abdominal pain, abdominal
tenderness, epigasMic discomfort, and gastrointestinal pain
Includes aphthous stomatitis, stomatitis, glossitis, mouth ulceration, and
mucosal inflammation
= Includes oral pain, glossodynia, and oropharyngeal pain
Includes asthenia, fatigue, and malaise
= Includes gingivitis, oral infection, parotitis, pericoronitis,
periodontitis, sialoadenitis, tooth abscess and
tooth infection
Includes musculoskeletal pain, back pain, pain in extremity, arthralgia, and
nayalgia =
= Includes prerenal failure, renal failure, acute renal failure, and renal
tubular necrosis
= Includes dyspnea, exertional dyspnea
Includes macular rash, maculo-papular rash, generalized rash, and rash
Includes hypertension, hypertensive crisis, increased diastolic blood pressure
and increased blood pressure
[0146] Some of the adverse events noted above are addressed below with
suggestions for
dealing with them.
[0147] Hypertension
In the trial described in Example 1, hypertension was reported in 43% of
patients in
the LENVIMATegistorca Trademark) everolimus-treated group (the incidence of
Grade 3 or
Grade 4 hypertension was 14%), 48% of patients in the LENVIMA(Registered
Trademark) _
treated group (the incidence of Grade 3 or Grade 4 hypertension was 17%), and
10% of
patients in the everolimus-treated group (the incidence of Grade 3 or Grade 4
hy-
pertension was 2%).
[0148] In view of these findings, it would be beneficial to control blood
pressure prior to
treatment of patients with LENV1MA(Registered Trademark) everolimus. The blood
pressure
of the patient should generally be monitored after 1 week, then every 2 weeks
for the
first 2 months, and then at least monthly thereafter during treatment with
LENVIMA
(Registered Trademark) everolimus. It would be advisable to withhold LENVIMA(
gigtred
Trademark) for Grade 3 hypertension despite optimal antihypeitensive therapy;
and to
resume at a reduced dose when hypertension is controlled at less than or equal
to
CA 03019682 2018-10-01
48
Grade 2. Furthermore, LENVIMA0145-aTr'demmk) should be discontinued for life-
threatening hypertension. Everolinius dose interruption or alternate day
dosing should
also be considered until toxicity resolves.
[0149] Patients undergoing treatment with LENVIMA(Regiatered Trademark)
everolimus should be
advised by the health care provider to undergo regular blood pressure
monitoring and
to contact their health care provider if their blood pressure is elevated.
[0150] Cardiac Dysfunction
In the trial described in Example 1, decreased ejection fraction and cardiac
failure
was reported in 4% (2% Grade 3) of patients in the LENVIMA(Registertd
Trademark) +
everolimus-treated group, 8% of patients in the LENVIMA(Registered Trademark)_
treated group
(2% Grade 3), and 4% of patients in the everolimus-treated group (2% Grade 3).
[0151] In view of these findings, it would be beneficial to monitor
patients for clinical
symptoms or signs of cardiac decompensation. It would also be advisable to
withhold
LENVIIVIA(Regiatered Trademark) for development of Grade 3 cardiac dysfunction
until
improved to Grade 0 or 1 or baseline. One could then either resume at a
reduced dose
or discontinue LENVIMA(Regialemd Trademark) depending on the severity and
persistence of
cardiac dysfunction. For Grade 4 cardiac dysfunction, LENVIMA(Regiatered
nademark) should
be discontinued. Everolimus dose interruption or alternate day dosing should
also be
considered until toxicity resolves.
[0152] Patients undergoing treatment with LENVIMAmegistered Trademark)
everolimus should be
advised by the health care provider that LENVIMA.gmteted Trademark) can cause
cardiac
dysfunction and to immediately contact their healthcare provider if they
experience
any clinical symptoms of cardiac dysfunction such as shortness of breath or
swelling of
ankles.
[0153] Arterial Thromboembolic Events
In the above-described trial, no arterial thromboembolic events were observed
in the
LENVIMM'egistered Trademark) + everolimus-treated group. 8% of patients in the
LENVIMA
(Registered Trademark)_ treated group (8% Grade 3 or greater) and 6% of
patients in the
everolimus-treated group (4% Grade 3 or greater) had arterial thromboembolic
events
reported.
[0154] LENVIMA(Registered Trademark) should be discontinued following an
arterial thrombotic
event.
10155] Patients undergoing treatment with LENVIMA(Regiatererl Trademark) +
everolimus should be
advised by the health care provider to seek immediate medical attention for
new onset
chest pain or acute neurologic symptoms consistent with myocardial infarction
or
stroke.
[0156] Hepatotoxicity
In the RCC trial described above, 4% of patients in the LENVIMAategister'd
Trademark) +
CA 03019682 2018-10-01
49
everolimus-treated group, 4% of patients in the LENVIMA(Registucd Tradcmark)_
treated
group, and 2% of patients in the everolimus-treated group experienced an
increase in
alanine aminotransferase (ALT) that was Grade 3 or greater. 4% of patients in
the
LENVEVIA(Registered Trademark) everolimus-treated group, 4% of patients in the
LENVIMA
(Registered Trademailo-treated group and no patients in the everolimus-treated
group ex-
perienced an increase in aspartate aminotransferase (AST) that was Grade 3 or
greater.
[0157] It is recommended that liver function be monitored before initiation of
LENVIMA
(Registered Trademark), then every 2 weeks for the first 2 months, and at
least monthly
thereafter during treatment. LENVIMA(egistered Trademark) should be withheld
for the de-
velopment of Grade 3 or greater liver impairment until resolved to Grade 0 to
1 or
baseline. One can then either resume at a reduced dose or discontinue LENVIMA
(Registered Trademark) depending on the severity and persistence of
hepatotoxicity. LENVIMA
(Registered Trademark) should be discontinued for hepatic failure.
[0158] Patients undergoing treatment with LENVIMA(Registered Trademark)
everolimus should be
advised by the health care provider to undergo lab tests to monitor for liver
function
and to report any new symptoms indicating hepatic toxicity or failure.
[0159] Proteinuria
In this RCC trial, proteinuria was reported in 24% of patients in the LENVIMA
(Registered Trademark) + everolimus-treated group (4% were Grade 3 or
greater), 31% of
patients in the LENVIIVIA Megi5t6TC'd Tradem.k)-treated group (19% were Grade
3 or greater),
and 14% of patients in the everolimus-treated group (2% were Grade 3 or
greater).
[0160] It is suggested that the healthcare provider monitor for proteinuria
before initiation
of, and periodically throughout treatment. If urine dipstick proteinuria
greater than or
equal to 2+ is detected, the health care provider should obtain a 24 hour
urine protein.
LENVIMA(Regigb:red Traµlemark) should be withheld for >=2 grams of
proteinuria/24 hours
and treatment with LENVIMA''ered Trademark) may be resumed at a reduced dose
when
proteinuria is <2 gm/24 hours. LENVIMA(Registered Trademark) should be
discontinued for
nephrotic syndrome.
[0161] Patients undergoing treatment with LENVIMA(Registered'rnd`rna'k)
everolimus should be
advised by the health care provider to undergo regular lab tests to monitor
for kidney
function and protein in the urine.
[0162] Renal Failure and Impairment/Diarrhea
Events of renal impairment were reported in 18% of LENVIMA(Registered
Trademark)
everolimus-treated group, 15% in the LENVIMA treed Trademark)_ treated group,
and
12% in the everolimus-treated group. The incidence of Grade 3 or greater renal
failure
or impairment was 8% in the LENVIMA(Registered Trademark) everolimus-treated
group, 6%
in the LENVIMA(Reestered Trad'mark)-treated group, and 2% in the everolimus-
treated group.
Grade 3 or greater diarrhea was reported in 22% of patients in the
LENVIMA(Registtred
CA 03019682 2018-10-01
Trademark) + everolimus-treated group, 12% of patients in the
LENVIIVIA(Registe,edTradcmark) -
treated group and 2% of patients in the everolimus-treated group.
[0163] The primary risk factor for severe renal impairment in
LENVIMA(Registered Trademark) _
treated patients was dehydration/hypovolemia due to diarrhea and vomiting.
Active
management of diarrhea and any other gastrointestinal symptoms should be
initiated
for Grade 1 events.
[0164] It is recommended that the health care provider withhold
LENVIMA(Registered Trademark)
upon development of Grade 3 or 4 renal failure/impairment until it has
resolved to
Grade 0 to 1 or baseline. One can then either resume at a reduced dose or
discontinue
LENNTIMA(Registered Trademark) depending on the severity and persistence of
renal im-
pairment.
[0165] Patients undergoing treatment with LENVIMA(Regiatered Trademark) +
everolimus should be
advised by the health care provider to undergo regular lab tests to monitor
for kidney
function and protein in the urine.
[0166] Gastrointestinal Perforation and Fistula Formation
In the RCC trial, events of gastrointestinal perforation or fistula were
reported in 2%
of patients in the LENVIMA(Reeatered Trademark) everolimus-treated group, 6%
in the
LENVIMA(Registered Trademark)_treated group, and no patients in the everolimus-
treated
group.
[0167] It is recommended that the health care provider discontinue
LENVIM_A(Registered Trademark)
in patients who develop gastrointestinal perforation or life-threatening
fistula.
[0168] Patients undergoing treatment with LENVIMA(Registered Trademark) +
everolimus should be
advised by the health care provider that LENVIMA(Registered Trademark) can
increase the risk
of gastrointestinal perforation or fistula and to seek immediate medical
attention for
severe abdominal pain.
[0169] QT Interval Prolongation
In the above-described trial, QT/QTc interval prolongation was reported in 6%
of
patients in both the LENVIMA(RclOsWcd Trademark) everolimus-treated group and
the
LEISWIMA(Registered TrademarkLtreated group. No Grade 3 or greater events were
reported in
either group. No reports of QT/QTe interval prolongation occurred in the
everolimus-
treated group.
[0170] In view of the above findings, it is recommended that the healthcare
provider monitor
electrocardiograms in patients with congenital long QT syndrome, congestive
heart
failure, bradyanhythmias, or those who are taking drugs known to prolong the
QT
interval, including Class la and HI antiarrhythmics. In addition, it is
recommended that
the healthcare provider monitor and correct electrolyte abnormalities in all
patients.
LENVIMA(Registered Trademark) should be withheld upon the development of Grade
3 or
greater QT interval prolongation. LENVIMA0Reg1""ed Trademark) administration
may be
CA 03019682 2018-10-01
51
resumed at a reduced dose when QT prolongation resolves to Grade 0 or 1 or
baseline.
[0171] Hypocalcemia
In the RCC trial, 6% of patients in the LENVIMA.ozeg'staeATrada'ark)
everolimus-treated
group, no patients in the LENVINUVRegistered nademarkLtreated group, and 2% of
patients in
the everolimus-treated group experienced Grade 3 or greater hypocalcemia.
[0172] Thus, it is recommended that patients be monitored for blood calcium
levels at least
monthly and that calcium be replaced as necessary during LENVIIVIAostexed
Trademark)
treatment. LENVIMA(Registered Trademark) dosing can be interrupted and
adjusted as
necessary depending on severity, presence of ECG changes, and persistence of
hypocalcemia.
[0173] Reversible Posterior Leukoencephalopathy Syndrome
In the RCC trial, one patient out of 103 who received either LEN VEVIA(R
egistered Trademark)
everolimus or LENVIMA(Registered Trademark) monotherapy experienced reversible
posterior leukoencephalopathy syndrome (RPLS).
[0174] It is prudent to confirm a diagnosis of RPLS with MRI and to
withhold for a
diagnosis of RPLS treatment with LENVIMA(Registered Trademark) until the RPLS
is fully
resolved. Upon resolution, administration of LENVIMA(Registemd Trademark) may
resume at a
reduced dose or discontinued depending on the severity and persistence of
neurologic
symptoms.
[0175] Hemorrhagic Events
In the RCC trial, hemorrhagic events occurred in 33% of patients in the
LENVIIVIA
(Regismred Trademark) everolimus-treated group (8% were Grade 3 or greater),
with the most
frequently reported hemorrhagic event being epistaxis (18% Grade 1 only).
Discon-
tinuation of treatment due to hemorrhagic events occurred in 4% of patients in
the
LENVIMA(Reoskred Trademark) + everolimus-treated group. In the
LENVIMA(Rcgistered Trademark) _
treated group, hemorrhagic events occurred in 29% of patients (2% were Grade 3
or
greater) with the most frequently reported hemorrhagic event being epistaxis
(8%
Grade 1 only). Discontinuation due to hemorrhagic events occurred in 2% of
patients
in the LENVYMATegistered TrademarkLtreated group. There was one case of fatal
cerebral
hemorrhage in the LENVIMA( ostaal Trademark) + everolimus-treated group and
one case
of fatal intracranial hemorrhage in the LENVIMATcostaa' Todcm"10-treated
group. In the
everolirnus-treated group, hemorrhagic events occurred in 28% of patients (2%
were
Grade 3 or greater) with the most frequently reported hemorrhagic event being
epistaxis (20% Grade 1, and 4% Grade 2 only). There were no discontinuations
due to
hemorrhagic events in the everolimus-treated group.
[0176] The healthcare provider should consider withholding
LENVIIVIA(Registered Trademark) for
the development of Grade 3 hemorrhage until resolved to Grade 0 to 1.
Treatment with
LENVIMA(Reg,istcred Trademark) may be resumed at a reduced dose or
discontinued
CA 03019682 2018-10-01
52
depending on the severity and persistence of hemorrhage. LENVIMA(Registered
Trademark)
treatment should be discontinued in patients who experience Grade 4
hemorrhage.
[0177] Patients undergoing treatment with LENVIMA(Registered Trademark) +
everolimus should be
advised by the hearth care provider that LENVIMA(Rgiatered Trademark) can
increase the risk
for bleeding and to contact their health care provider for bleeding or
symptoms of
severe bleeding.
[0178] Impairment of Thyroid Stimulating Hormone SuppressionfThyroid
Dysfunction
In the RCC trial, hypothyroidism occurred in 24% of patients in the LENVIMA
(Registered Trademark) everolimus-treated group, 37% of patients in the
LENVIMA(Regio"cd
Tradcmark)-treated group, and 2% of patients in the everolimus-treated group.
All events of
hypothyroidism in the LENVIMA(Registered Trademark) everolimus-treated group
were of
Grade 1 or 2.
[0179] 75% of patients in the LENVIMA(Regiatemd Trademark) + everolimus-
treated group were not
receiving exogenous thyroid replacement, and of these, 71% had normal baseline
TSH
levels. In patients with a normal TSH at baseline, an elevation of TSH level
was
observed post baseline in 63% of LENVIMA(Registered Trademark) everolimus-
treated
patients as compared with none in patients receiving everolimus alone.
[0180] Thyroid function should be monitored before initiation of, and
periodically
throughout, treatment with LENVIMA. Hypothyroidism should be treated according
to
standard medical practice to maintain euthyroid state.
[0181] Embryofetal Toxicity
Based on its mechanism of action and data from animal reproduction studies,
LENVIMAOtegiatemd Trademark) can cause fetal harm when administered to a
pregnant
woman. In animal reproduction studies, oral administration of lenvatinib
during
organogenesis at doses below the recommended human dose resulted in embry-
otmdcity, fetotoxicity, and teratogenicity in rats and rabbits.
[0182] Accordingly, the healthcare provider must advise pregnant women of
the potential
risk to a fetus. In addition, in the case of females of reproductive
potential, the
healthcare provider should advise the patient to use effective contraception
during
treatment with LENVIMA(Regimmed Trademark) and for at least 2 weeks following
completion
of therapy.
[0183] Patients undergoing treatment with LENVIMA(Reg'sr'red Trademark)
everolimus should be
advised by the health care provider to inform their healthcare provider of a
known or
suspected pregnancy.
[0184] Table 3 provides a summary of laboratory abnormalities observed in
the patients in
the RCC trial described in Example 1.
[0185]
CA 03019682 2018-10-01
53
[Table 4]
Table 3: Laboratory Abnormalities with at Least Greater than or equal to 3% in
Grade 3 or 4 Events in LENVIMA + Everolimus-Treated Patients"
Laboratory Abnormality LENV1MA 10mg LENV1MA Everolimus
+ Everolimus 5mg 24mg 10mg
N=51 N=52 N=50
Grades 3-4 Grades 3-4 Grades 3-4
(%) (%) (%)
Chemistry
Aspartate aminotransferase 4 4
(AST) increased
Alanine aminotransferase (ALT) 4 2
4
increased
Alkaline phosphatase increased 4 0 0
Hyperkalernia 6 2 2
Hypokalemia 8 8 2
Hyponatrernia 10 6 6
Hypocaleemia 6 0 2
Hypophosphatemia 14 4 6
Hyperglycemia 4 8 16
Hypertriglyceridemia 14 10 18
High cholesterol 12 4 0
Lipase increased 16 10 12
Hematology
Hemoglobin decreased 8 4 16
Platelet count decreased 6 2 0
Lymphocyte count decreased 6 4 20
a With at least 1 grade increase front baseline
b Subject with at least I post baseline laboratory value
[0186] Cross-Reference to Related Applications
This application claims priority to U.S. Provisional Appl. No. 62/322,916, and
Japanese Patent Application No. JP2016-081787, both filed on April 15, 2016,
the
content of both of which are incorporated by reference herein in their
entirety.
[0187] Other Embodiments
While the invention has been described in conjunction with the detailed
description
thereof, the foregoing description is intended to illustrate and not limit the
scope of the
invention, which is defined by the scope of the appended claims. Other
aspects, ad-
vantages, and modifications are within the scope of the following claims.
