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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
"fever"
symptom
22q11.2 deletion syndrome
acute rheumatic fever
alexander disease
allergic bronchopulmonary aspergillosis
canavan disease
carcinoma of the gallbladder
child syndrome
congenital toxoplasmosis
cushing syndrome
cystinuria
dracunculiasis
erdheim-chester disease
esophageal adenocarcinoma
esophageal carcinoma
familial mediterranean fever
focal myositis
hodgkin lymphoma, classical
lamellar ichthyosis
legionellosis
locked-in syndrome
malignant atrophic papulosis
neonatal adrenoleukodystrophy
neuralgic amyotrophy
oculocutaneous albinism
papillon-lefèvre syndrome
pyomyositis
pyruvate dehydrogenase deficiency
scrub typhus
severe combined immunodeficiency
sneddon syndrome
systemic capillary leak syndrome
triple a syndrome
typhoid
waldenström macroglobulinemia
wolf-hirschhorn syndrome
This symptom has already been validated