Phase 1/2 Study of Elotuzumab in
Combination with Lenalidomide and Low
Dose Dexamethasone in Relapsed or
Refractory Multiple Myeloma: Interim Results
Sagar Lonial1, Ravi Vij2, Jean-Luc Harousseau3, Thierry Facon4, Jonathan
Kaufman1, Amitabha Mazumder5, Philippe Moreau3, Xavier Leleu4, John
Fry6, Anil Singhal6 and Sundar Jagannath5
1Winship Cancer Institute, Emory University, Atlanta, GA; 2Oncology, Washington
University School of Medicine, Saint Louis, MO; 3Hematology, CHU Hotel-Dieu,
Nantes, France; 4Service des maladies du sang, Hospital Claude Huriez, CHRU
Lille, Lille, France; 5St. Vincent's Comprehensive Cancer Center, New York, NY;
6Facet Biotech, Redwood City, CA
1
Disclosures for Dr. Sagar Lonial
Research Support
Millenium
Employee
N/A
Consultant
Millenium, Celgene,
BMS/Facet, Novartis
Major Stockholder
N/A
Speakers' Bureau/Scientific
N/A
Advisory Board
2
Elotuzumab
A humanized monoclonal IgG1 targeting CS1, a cell surface glycoprotein
CS1 is highly and uniformly expressed on multiple myeloma cells, with
restricted expression on NK cells and little to no expression on normal
tissues
Pre-clinical data indicates mechanism of action is mainly through NK-
mediated ADCC
Elotuzumab monotherapy study in advanced MM patients exhibited a
manageable safety profile (first dose infusion reactions were key AEs) and
stable disease in a number of patients
20/20 bone marrow cores were positive for CS1 expression
Hsi et al., Clin Cancer Res 14:2775, 2008
3
Anti-tumor Activity of Elotuzumab is Enhanced by
Lenalidomide in Myeloma Xenograft Mouse Model
600
500
)3
400
(mm
lenalidomide dosing
elotuzumab or control IgG1 dosing
300
Control IgG1 + DMSO
volume
Elotuzumab + DMSO
200
Len + control IgG
Len + Elo
Tumor
100
014
21
28
35
42
Study Day
Elotuzumab was given at a dose of 1 mg/kg (below the maximum
efficacious dose of 10 mg/kg)
Lenalidomide was given at 50 mg/kg
4
Dosing Regimen
DLT
Response
Observation
Assessments
Elotuzumab
Dosing
CYCLE 1
CYCLE 2
CYCLE 3
CYCLE 4
CYCLE 5
N-1
CYCLE 6
N
Lenalidomide
dai
dai ly
y dos
do e
se
daily dose
dai
dai ly
y dos
do e
se
dai
dai ly
y dos
do e
se
daily dose
dai
dai ly
y dos
do e
se
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
3+3 dose escalation cohorts evaluating 5, 10, and 20 mg/kg
elotuzumab in combination with 25 mg lenalidomide and low dose
dexamethasone
First 5 patients were limited to 6 cycles of treatment. Remaining 23
patients are being treated until disease progression or unacceptable
toxicity, if earlier
5
Study Objectives
Primary objective
Establish the MTD* of elotuzumab in combination
with lenalidomide and low dose dexamethasone
Secondary objectives
Evaluate the pharmacokinetics of elotuzumab
Evaluate the efficacy of elotuzumab in combination
with lenalidomide and low dose dexamethasone
Evaluate the immunogenicity of elotuzumab
Explore pharmacodynamic markers of elotuzumab
* The MTD is defined as the highest dose level of elotuzumab at which 1 of 6
subjects experienced a DLT
6
Key Eligibility Criteria
INCLUSION
Relapsed multiple myeloma with one or more prior therapies
Measurable disease M protein of 0.5 g/dL in serum and/or 0.2 g in
24 hr urine collection sample
ECOG performance status = 0-2
ANC > 1,000 cells/mm3; Platelets 75,000 cells/mm3; Hgb 8 g/dL
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 stem-cell transplant within 12 weeks
Treatment with nitrosoureas or melphalan within 6 weeks
Neuropathy Grade 2
7
Baseline Characteristics
Characteristics
N=29
Median Age (range)
60 (41-83)
Median time since first diagnosis (range)
5.2 (1.1-12.9) years
Median myeloma stage
Stage III
Median no. of prior lines of therapy (range)
3 (1-10)
Prior transplant
21 (72%)
Refractory from the last treatment
12 (41%)
High risk based on cytogenetics
3 (13%)
Prior bortezomib
20 (69%)
Prior thalidomide
17 (59%)
Prior lenalidomide
6 (21%)
8
Patient Disposition
Total dosed
28
Total DLTs in dose escalation phase
0
Still on study medication
18
Median number of cycles (range)
4.5 (1-11)
Reasons for withdrawal:
End of study (6 cycles)*
4
Disease progression1
2
Elotuzumab infusion reaction
2
Investigator decision
1
Missing (treatment cessation not in database)1
1
*Initial study design limited 5 patients to 6 cycles of treatment. Two patients progressed during 60 day
post-treatment follow-up
1Based on data-cut-off as of Nov. 3, 2009.
9
Safety
Regardless of relationship to study drugs (N=28)
All Grade 3/4 and SAEs
Neutropenia
Thrombocytopenia
Fatigue
Anaphylatic reaction
SAE related to elotuzumab
Musculoskeletal chest pain
Stridor
SAE related to elotuzumab
Deep vein thrombosis
Diverticular perforation
SAE
Adverse Events (all grades) 14%
Blood phosphurus decreased
Fatigue
Febrile neutropenia
SAE
Diarrhoea
Diarrhoea
SAE
Constipation
Anaemia
Anaemia
Neutropenia
Constipation
Nausea
Haemoglobinaemia
Muscle spasms
Leukopenia
Pyrexia
Asthenia
Lymphopenia
Dyspnoea
Renal failure
Thrombocytopenia
Pneumonia
Chills
Influenza
Insomnia
Arthralgia
Memory impairment
Back pain
Hypokalaemia
Neuropathy peripheral
Atrial fibrillation
SAE
Rash
Sepsis
SAE
0%
10%
20%
30%
40%
50%
60%
Enteritis
SAE
% of patients
0%
5%
10%
15%
20%
% of patients
10
Elotuzumab Pharmacokinetics and
CS1 Target Saturation
Pharmacokinetics
10mg/kg simulation
20mg/kg simulation PK model developed using
L) 1000
available data from 1703 and
monotherapy study
erum
cg/m
S
m(
ab
Trough concentrations at 10 and 20
ion 100
rat
mg/kg are above target of 70 µg/ml
uzum
70ug/mL
lot
ent
based on preclinical xenograft
E
onc
models
C
10 0 28 56 84 112 140 168 196 224 252
Time (day)
CS1 Target Saturation
100 95%Emax
Saturation of CS1 on bone marrow
myeloma cells was done by flow
80
ls
cytometry
el
Elotuzumab
C
60
by
Complete target saturation was
40
seen at doses of 5 and 10 mg/kg
CS1
5 mg/kg
of
Myeloma
10 mg/kg
Testing at 20 mg/kg is in progress
20
BMon
0
Saturation
10
100
1000
%
Serum Concentration of elotuzumab, g/ml
11
Efficacy
Best Confirmed Response
Patients w/o prior
Total Patients (%)
lenalidomide
Total treated
28
22
population1
ORR (PR)2
23 (82%)
21 (95%)
VGPR
5 (18%)
5 (23%)
PR
18 (64%)
16 (73%)
SD
4 (14%)
1 (4%)
PD
0
0
NE
1 (4%)
0
1 Patients receiving one or more doses of elotuzumab
2 Response assessed by IMWG criteria
12
Efficacy
Best Confirmed Response
Refractory to
Total
Prior
Prior
most recent
Patients
thalidomide
bortezomib3
MM treatment
(%)
(%)
(%)
(%)
Total treated
28
16
20
12
population1
ORR (PR)2
23 (82%)
15 (94%)
15 (75%)
10 (83%)
VGPR
5 (18%)
4 (25%)
3 (15%)
3 (25%)
PR
18 (64%)
11 (69%)
12 (60%)
7 (58%)
SD
4 (14%)
1 (6%)
4(20%)
2 (17%)
PD
0
0
0
0
NE
1 (4%)
0
1 (5%)
0
1 Patients receiving one or more doses of elotuzumab
2 Response assessed by IMWG criteria
3 4/5 non-responding patients also received prior lenalidomide
13
ORR by Prior Lines of Therapy
Lenalidomide-naïve
All treated patients
Prior lines of
patients
therapy
Total
Total
ORR (%)
ORR (%)
Patients
Patients
1
7
6 (86%)
6
6 (100%)
2
21
17 (81%)
16
15 (94%)
Median: 3
28
23 (82%)
22
21 (95%)
Range: 1-10
14
Time to Disease Progression
After a median of 4.5 months of follow-up:
4 out of 28 subjects progressed (2 progressions during post-treatment
follow-up)
Median TTP has not been reached
PD
without
Subjects
of%
Days
15
Summary
Interim data from 28 treated patients with a median of 3 prior
MM treatments demonstrated an acceptable safety profile:
No DLTs were observed in the dose-escalation phase
and the MTD was not reached up to the highest dose of
20 mg/kg
Two patients experienced elotuzumab associated SAEs
of infusion reaction
23/28 (82%) patients including 21/22 (95%) lenalidomide-
naïve patients achieved PR in the study
Phase 2 expansion is being initiated to further examine the
efficacy and identify the optimal dose of elotuzumab (10 vs.
20 mg/kg) in combination with lenalidomide and low dose
dexamethasone
16
Acknowledgements
We would like to thank patients and their families
Susan Kelley
Ajai Chari
Robert Frumento
Chris Westland
Richard Brotherton
Daniel Afar
Jean-Luc Harousseau
L.T. Heffner
Phillipe Moreau
Carol Zhao
Dixil Francis
Han Ding
Jan van Tornout
Audie Rice
Lille University Hospital
David Berman
Balaji Balasa
Thierry Facon
Susan Galbraith
Mel Fox
Xavier Leleu
Claire Tsao
Svetlana Lucas
Matt Williams
Ravi Vij
D. Gensbourg
17