AT A GLANCE
Clinical trial OSU-10054
PI:
DON M. BENSON JR., MD, PHD, assistant professor of Medicine,
Division of Hematology
Phone:
614-293-8605
Email:
don.benson@osumc.edu
Eligibility:
Patients with
progressive or relapsed multiple
myeloma after one prior
therapeutic treatment with
response duration of at least
six months; prior treatment
regimens may have included
lenalidomide and thalidomide;
if previously treated with
lenalidomide, the subject must
not have progressed during
treatment and must not have
discontinued the drug due to
intolerance; measurable disease;
ECOG 0,1, or 2; clinical lab values
at screening; FCBP must have
negative pregnancy test 10-14
days prior to and again within 24
hours of prescribing lenalidomide
and agree to use 2 methods of
birth control; must be registered
and willing to comply with
requirements of RevAssist.
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OSU-10054 – A Multicenter Phase I/II Study on the Anti-Tumor Activity,
Safety and Pharmacology of IPH2101, a Human Monoclonal Anti-KIR,
Combined with Lenalidomide in Patients with Multiple Myeloma
Experiencing a First Relapse
HYPOTHESIS:
The combination
of lenalidomide and IPH2101 is
safe, and the agents in combination
show clinical activity in patients
experiencing a first relapse of
multiple myeloma.
RATIONALE:
Multiple myeloma
(MM) is a malignancy of plasma
cells. Treatment involves chemotherapy
with high-dose corticosteroids
or high-dose melphalan
with stem cell rescue for selected
patients. Targeted drugs, including
the immunomodulatory agent
lenalidomide, are broadening
patients' therapeutic options.
Nonetheless, MM remains incurable,
with relapses invariably occurring
a median of 24 to 30 months
following stem cell transplant.
NK cells, large granular lymphocytes
that play a crucial role in
cellular innate immunity and tumor
cell killing, play an important role
in controlling MM, but this ability
is gradually lost during disease
progression. Recent data suggests
that lenalidomide can help restore
the ability of NK cells to kill MM
cells.
Lenalidomide's mechanism of
action against MM is not understood,
but evidence suggests there are
several. The agent may work directly
on MM cells by inducing apoptosis
or arresting growth. Perhaps more
significantly, lenalidomide
stimulates T-cell proliferation,
which leads to increased IL-2 and
IFN-gamma secretion. These
circulating cytokines then boost
NK cell numbers and activity and
increase MM cell death.
Cell killing by NK cells is tightly
regulated by killer immunoglobulinlike
receptors (KIR) displayed on
the cell surface. There are both
inhibitory and activating KIR.
Inhibitory KIR generally outnumber,
and bind cellular ligands more
readily than, activating KIR, and
this can prevent NK-cell killing
even when activating signals are
present.
IPH2101 is a novel therapy that
may reduce this effect. Data suggest
that this human monoclonal
antibody binds to inhibitory KIR
and blocks inhibitory signaling,
thereby increasing MM cell killing
by NK cells. Clinical studies indicate
that the agent is well tolerated by
patients.
Collectively, the evidence suggests
that IPH2101 and lenalidomide
have additive or synergistic
mechanisms of action and supports
their development as a promising,
novel, steroid-sparing combination
therapy for patients with MM.
Moreover, the effect is specific to
the MM tumor cell clone. NK cell
cytotoxicity assays of the agents
on normal peripheral blood
mononuclear cells have shown no
increase in killing.