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Phase I clinical trial combining imatinib mesylate and IL-2 in refractory cancer patients: IL-2 interferes with the pharmacokinetics of imatinib mesylate.
[systemic capillary leak syndrome]
Imatinib
mesylate
(
IM
)
is
a
small
molecule
inhibitor
of
protein
tyrosine
kinases
.
In
addition
to
its
direct
effect
on
malignant
cells
,
it
has
been
suggested
IM
may
activate
of
natural
killer
(
NK
)
cells
,
hence
exerting
immunomodulatory
functions
.
In
preclinical
settings
,
improved
antitumor
responses
have
been
observed
when
IM
and
interleukin-
2
(
IL
-
2
)
,
a
cytokine
that
enhances
NK
cells
functions
,
were
combined
.
The
goals
of
this
study
were
to
determine
the
maximum
tolerated
dose
(
MTD
)
of
IL
-
2
combined
with
IM
at
a
constant
dose
of
400
mg
,
the
pharmacokinetics
of
IM
and
IL
-
2
,
as
well
as
toxicity
and
clinical
efficacy
of
this
immunotherapeutic
regimen
in
patients
affected
by
advanced
tumors
.
The
treatment
consisted
in
50
mg
/
day
cyclophosphamide
from
21
d
before
the
initiation
of
IM
throughout
the
first
IM
cycle
(
from
D-
21
to
D
14
)
,
400
mg
/
day
IM
for
14
d
(
D
1
to
D
14
)
combined
with
escalating
doses
of
IL
-
2
(
3
,
6
,
9
and
12
MIU
/
day
)
from
days
10
to
14
.
This
treatment
was
administered
at
three
week
intervals
to
17
patients
.
Common
side
effects
of
the
combination
were
mild
to
moderate
,
including
fever
,
chills
,
fatigue
,
nausea
and
hepatic
enzyme
elevation
.
IL
-
2
dose
level
II
,
6
MIU
/
day
,
was
determined
as
the
MTD
with
the
following
dose-limiting
toxicities
:
systemic
capillary
leak
syndrome
,
fatigue
and
anorexia
.
Pharmacokinetic
studies
revealed
that
the
area
under
the
curve
and
the
maximum
concentration
of
IM
and
its
main
metabolite
CGP
74588
increased
significantly
when
IM
was
concomitantly
administered
with
IL
-
2
.
In
contrast
,
IM
did
not
modulate
IL
-
2
pharmacokinetics
.
No
objective
responses
were
observed
.
The
best
response
obtained
was
stable
disease
in
8
/
17
(
median
duration
:
12
weeks
)
.
Finally
,
IL
-
2
augmented
the
impregnation
of
IM
and
its
metabolite
.
The
combination
of
IM
(
400
mg
/
day
)
and
IL
-
2
(
6
MIU
/
day
)
in
tumors
that
express
IM
targets
warrants
further
investigation
.
Diseases
Validation
Diseases presenting
"malignant cells"
symptom
focal myositis
hodgkin lymphoma, classical
oral submucous fibrosis
pleomorphic liposarcoma
severe combined immunodeficiency
systemic capillary leak syndrome
waldenström macroglobulinemia
werner syndrome
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