Elotuzumab in Combination With
With
Lenalidomide and Low-Dose
Dexamethasone in Relapsed
p
or
Refractory Multiple Myeloma:
A Phase 1/2 Study
S Lonial,1,2 R Vij,1,3 JL Harousseau,4 T Facon,5 P Moreau,6
X Leleu,5 C Westland,7 AK Singhal,7 S Jagannath1,8
1Multiple Myeloma Research Consortium, Norwalk, CT, USA; 2Emory University
School of Medicine, The Winship Cancer Institute, Atlanta, GA, USA; 3Washington
University School of Medicine, St. Louis, MO, USA; 4Centre René Gauducheau,
Nantes, France; 5Hôpital Claude Huriez, Service des Maladies du Sang, Lille, France;
6Hematology Department, University Hospital, Nantes, France; 7Facet Biotech,
Redwood City, CA, USA; 8St. Vincent's Comprehensive Cancer Center, New York, NY,
USA
Elotuzumab + Lenalidomide + Low-Dose Dexamethasone in Multiple Myeloma, Phase 1/2
Disclosures
Consultant/Advisory Role
Bristol-Myers Squibb
Squibb Company, Celgene Corporation,
Facet Biotech, Millennium Pharmaceuticals, and Novartis
Research Funding
Bristol-Myers Squibb Company, Celgene Corporation,
Facet Biotech,
Biotech, Gloucester
Gloucester Pharmaceuticals,
Pharmaceuticals, Millennium
Pharmaceuticals, and Novartis
2
Elotuzumab + Lenalidomide + Low-Dose Dexamethasone in Multiple Myeloma, Phase 1/2
Elotuzumab
Humanized monoclonal IgG1 antibody targeting human CS1, a cell surface
glycoprotein1,2
CS1: highly and uniformly expressed on MM cells, restricted expression on
NK cells, little to no expression on normal tissues1­3
Preclinical data indicate MOA is mainly through NK-mediated ADCC1,2
Elotuzumab monotherapy exhibited a manageable safety profile and SD in
a number of patients with advanced MM4
Key toxicities included infusion reactions such as chills, pyrexia,
headache, flushing, nausea, and vomiting
20/20 MM bone marrow cores and 8/8 plasmacytomas were positive for
CS1 expression1
ADCC, antibody-dependent cellular cytotoxicity; MM, multiple myeloma; MOA, mechanism of action; NK, natural killer; SD, stable disease.
1Hsi ED et al. Clin Cancer Res. 2008;14:2775-2784; 2Tai YT et al. Blood. 2008;112:1329-1337; 3van Rhee F et al. Mol Cancer Ther.
2009;8:2616-2624; 4Zonder JA et al. Blood. 2008;112:2773.
3
Elotuzumab + Lenalidomide + Low-Dose Dexamethasone in Multiple Myeloma, Phase 1/2
Antitumor Activity of Elotuzumab Is Enhanced by
Lenalidomide in
in Myeloma
Myeloma Xenograft
Xenograft Mouse Model1
Model
600
500
3
400
mm
Lenalidomide dosing
e,
Elotuzumab or control IgG1 dosing
m 300
olu
Control IgG1 + DMSO
V
Elotuzumab + DMSO
200
Lenalidomide + control IgG1
umor
Elotuzumab + lenalidomide
T
100
0 14
21
28
35
42
Study Day
Elotuzumab dosed at 1 mg/kg (below the maximum efficacious dose of
10 mg/kg)
Lenalidomide dosed at 50 mg/kg
1Lonial S et al. Blood. 2009;114:432.
4
Elotuzumab + Lenalidomide + Low-Dose Dexamethasone in Multiple Myeloma, Phase 1/2
Study Obj
yjectives
Phase 1b
Primary objective
Establish MTD* of elotuzumab in combination with lenalidomide and
low-dose dexamethasone
Secondary objectives
Evaluate efficacy of elotuzumab in combination with lenalidomide and
low-dose dexamethasone
Evaluate pharmacokinetics of elotuzumab
Explore pharmacodynamic markers of
of elotuzumab
elotuzumab
Evaluate immunogenicity of elotuzumab
Phase 2
Primary objective
Evaluate the safety and efficacy of elotuzumab at 2 different doses
Optimize premedication regimen of elotuzumab
*MTD = highest dose level of elotuzumab at which 1 of 6 subjects experienced a dose-limiting toxicity.
MTD, maximum tolerated dose.
5
Elotuzumab + Lenalidomide + Low-Dose Dexamethasone in Multiple Myeloma, Phase 1/2
Phase 1b/2 Study Schema
DLT
Response
Observation
Assessments
Elotuzumab
Di
Dosing
CYCLE 1
CYCLE 2
CYCLE 3
CYCLE 4
CYCLE 5
N-1
CYCLE 6
N
Lenalidomide
daily
daily dose
dose
daily dose
daily
daily dose
dose
daily
daily dose
dose
daily dose
daily
daily dose
dose
Cycle day:
1
8
15
22
1
8
15
22
1
8
15
22
1
8
15
22
1
8
15
22
1
8
15
22
28
Dexamethasone
Phase 1b 3+3 dose escalation cohorts evaluating elotuzumab 5, 10,
and 20 mg/kg IV
IV in
in combination
combination with lenalidomide
lenalidomide 25
25 mg
mg PO
PO and
low-dose dexamethasone PO
First 5 patients limited to 6 cycles of therapy; remaining 23 treated
until disease progression or unacceptable toxicity, if earlier
Phase 2 randomi i
z ng (1 1)
:
i
approx
t
ma l
e y 60
60
t
pa iti t
en s to i
e th
ither
10 or 20 mg/kg elotuzumab
DLT, dose-limiting toxicity.
6
Elotuzumab + Lenalidomide + Low-Dose Dexamethasone in Multiple Myeloma, Phase 1/2
Phase 1b: Key Eligibilit
yg
y Criteria
Inclusion
Relapsed MM with 1 prior therapies
Measurable disease by M protein
Creatinine clearance 50 mL/min (Cockcroft-Gault method)
Exclusion
Thalidomide, bortezomib, or corticosteroids within 2 weeks of the
first dose
Prior lenalidomide within 6 weeks of the first dose (prior
lenalidomide therapy excluded in Phase 2)
7
Elotuzumab + Lenalidomide + Low-Dose Dexamethasone in Multiple Myeloma, Phase 1/2
Phase 1b: Baseline Characteristics
N=29
Age, median
median (range)
60 (41­83)
Years since first diagnosis, median (range)
5.2 (1.1­12.9)
Myeloma stage,
stage, median
Stage III
Prior therapies, median (range)
3 (1­10)
Prior lenalidomide, n (%)
6 (21)
Prior bortezomib, n (%)
20 (69)
Prior thalidomide, n (%)
17 (59)
Prior transplant (autologous), n (%)
21 (72)
Refractory to last therapy, n (%)
12 (41)
High risk based on cytogenetics*, n (%)
3 (13)
*Defined as -13 by metaphase or t(4;14), t(14;16) or 17p del by fluorescence in situ hybridization (FISH).
8
Elotuzumab + Lenalidomide + Low-Dose Dexamethasone in Multiple Myeloma, Phase 1/2
Phase 1b: Patient Disposition*
p
Total enrolled and dosed
28
Total DLTs in dose escalation phase
0
Still on study (receiving study drug)
12
Reasons for withdrawal
End of study (initial protocol)
4
Disease progression
7
Adverse event
4
Patient decision
1
*Data as of May 11, 2010.
9
Elotuzumab + Lenalidomide + Low-Dose Dexamethasone in Multiple Myeloma, Phase 1/2
Phase 1b:
Adverse Events Regardless of Relationship ­
All Grades
Grades 20% and Grade
Grade 3/4 (N=
(N 28, dosed)
Fatigue
Anemia
Diarrhea
Nausea
Constipation
Neutropenia
All grades, %
Grade 3/4, %
Muscle spasms
Pyrexia
Insomnia
Back pain
Hypokalemia
Elotuzumab-related infusion reactions: one
episode each of
of Grade
Grade 4 hypersensitivity
hypersensitivity
Arthralgia
and Grade 3 stridor
Asthenia
Headache
Thrombocytopenia
0
10
2030
405060
7080
90
100
10
Elotuzumab + Lenalidomide + Low-Dose Dexamethasone in Multiple Myeloma, Phase 1/2
Phase 1b: Efficacy
Best Confirmed Respon
espo se
se (IMWG Criteri
te a)
Lenalidomide-Nave
Total Patients (%)
Patients (%)
Total ITT population
28
22
ORR ( PR)
23
(82)
21
(95)
CR
1
(4)
1
(5)
VGPR
7
(25)
6
(27)
PR
15
(54)
14
(64)
SD
4
(14)
1
(5)
PD
1
(4)
0
CR, complete response; IMWG, International Myeloma Working Group; ITT, intent-to-treat; ORR, objective response rate; PD,
progressive disease; PR, partial response; VGPR, very good partial response.
11
Elotuzumab + Lenalidomide + Low-Dose Dexamethasone in Multiple Myeloma, Phase 1/2
Phase 1b: Efficacy
Best Confirmed Respon
espo se
se (IMWG Criteri
te a)
Total
Prior
Prior
Refractory to
Patients Thalidomide Bortezomib Most Recent MM
(%)
(%)
(%)
Therapy (%)
Total patients
28
16
20
12
ORR ( PR)
23 (82)
15 (94)
15 (75)
10 (83)
CR
1
(4)
0
1
(5)
0
VGPR
7
(25)
()
6
(38)
()
3
(15)
()
3
(25)
()
PR
15 (54)
9
(56)
11 (55)
7
(58)
SD
4
(14)
1
(6)
4
(20)
2
(17)
PD
1
(4)
0
1
(5)
0
1 of
of 2 lenalidomide-refractory patients achieved
achieved a PR
12
Elotuzumab + Lenalidomide + Low-Dose Dexamethasone in Multiple Myeloma, Phase 1/2
Time to Disease Progression
g
Follow-up is short; median follow-up 32 weeks (range:
9­64 weeks)
11 patients progressed (39%); median TTP not reached
TTP, time-to-progression.
13
Elotuzumab + Lenalidomide + Low-Dose Dexamethasone in Multiple Myeloma, Phase 1/2
Phase 2 Expansion
p
60 patients being randomized (1:1) to either 10 or 20 mg/kg
elotuzumab
12 patients dosed with one or more cycles
No severe or serious elotuzumab-related events
New infusion
infusion premedication
premedication regimen initiated
initiated
No serious infusion reactions have occurred with premedication
14
Elotuzumab + Lenalidomide + Low-Dose Dexamethasone in Multiple Myeloma, Phase 1/2
Phase 2: Complete Saturation of CS1 by Elotuzumab
Observ
Obse ed on
o Bon
o e Marr
a ow
o Mye
y l
e om
o a Ce
C ll
e s
Complete target saturation at doses of 10 and 20 mg/kg
15
Elotuzumab + Lenalidomide + Low-Dose Dexamethasone in Multiple Myeloma, Phase 1/2
Conclusions
Elotuzumab + lenalidomide + low-dose dexamethasone
demonstrated a manageable safety
gy profile
p
in the Phase 1b
study in 28 treated patients with a median of 3 prior MM
therapies
No DLTs observed in
in the
the dose-escalation
-
phase
Additional toxicities (not Rd related) appear to be infusion
reactions
PR or b t
e ttter in 23/28 (82%)
t
pa iti t
en s incl di
u ng 21/22 (95%)
lenalidomide-nave patients
Phase 2 expansion is ongoing to identify the optimal dose of
elotuzumab (10 vs 20 mg/kg) in combination with
lenalidomide and low-dose dexamethasone (NCT00742560)
16
Elotuzumab + Lenalidomide + Low-Dose Dexamethasone in Multiple Myeloma, Phase 1/2
Acknowledgments
g
Emory University School of Medicine, The Winship Cancer Institute
Washington University
gy School of Medicine
Centre René Gauducheau, Nantes, France
Hôpital Claude Huriez, Service des Maladies du Sang, Lille, France
Ui
Universitity Hospitl
ital, N t
an es, France
St. Vincent's Comprehensive Cancer Center
Facet Biotech (a wholly-owned subsidiary of Abbott)
Danny Afar, Han Ding, John Fry, Lauri Neyer, Claire Tsao
Bristol-Myers Squibb Company
The patients and
and their families
families
17
Elotuzumab + Lenalidomide + Low-Dose Dexamethasone in Multiple Myeloma, Phase 1/2
Additional Acknowledgments
g
Phase 2 investigators
N Bahlis
Bahlis
G Morgan
Morgan
L Benboubker
M Raab
F Davies
D Reece
HG
H h
Ghesquieres
PG Richardson
H Goldschmidt
JF Rossi
M Gramatzki
E Tholouli
A Jakubowiak
D White
J Kaufman
J Wolf
A Mazumder
Mazumder
J Zonder
Zonder
18