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CLINICAL TRIALS AND OBSERVATIONS
A phase 1, multicenter, open-label, dose escalation study of elotuzumab in patients
with advanced multiple myeloma
Jeffrey A. Zonder,1 Ann F. Mohrbacher,2 Seema Singhal,3 Frits van Rhee,4 William I. Bensinger,5 Han Ding,6 John Fry,6
Daniel E. H. Afar,6 and Anil K. Singhal6
1Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI; 2Norris Comprehensive Cancer Center, University of Southern California,
Los Angeles, CA; 3Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL; 4Myeloma Institute for Research and Therapy,
University of Arkansas for Medical Sciences, Little Rock, AR; 5Fred Hutchinson Cancer Research Center, Seattle, WA; and 6Facet Biotech (now Abbott
Biotherapeutics Corp), Redwood City, CA
This multicenter, first-in-human study
evaluated the safety, tolerability, and pharmacokinetic and pharmacodynamic properties of the anti-CS1 monoclonal antibody elotuzumab. A standard 3 ⴙ 3 design
was used to determine maximum tolerated dose; dose-limiting toxicities were
assessed during cycle 1. Thirty-five patients with relapsed/refractory multiple
myeloma were treated with intravenous
elotuzumab at doses ranging from 0.5 to
20 mg/kg every 2 weeks. Patients who
achieved at least stable disease after
4 treatments could receive another 4 treatments. No maximum tolerated dose was
identified up to the maximum planned
dose of 20 mg/kg. The most common
adverse events, regardless of attribution,
were cough, headache, back pain, fever,
and chills. Adverse events were generally
mild to moderate in severity, and adverse
events attributed to study medication
were primarily infusion-related. Plasma
elotuzumab levels and terminal half-life
increased with dose whereas clearance
decreased, suggesting target-mediated
clearance. CS1 on bone marrow–derived
plasma cells was reliably saturated
(> 95%) at the 10-mg/kg and 20-mg/kg
dose levels. Using the European Group
for Bone and Marrow Transplantation myeloma response criteria, 9 patients (26.5%)
had stable disease. In summary, elotuzumab was generally well tolerated in this
population, justifying further exploration
of this agent in combination regimens.
(Blood. 2012;120(3):552-559)
Introduction
Multiple myeloma (MM) is an incurable malignancy arising from
postgerminal mature B cells, characterized by an excess of
monotypic plasma cells in the bone marrow and elevated levels of
monoclonal immunoglobulins in the serum and/or urine.1 Common
clinical sequelae include lytic bone lesions, fractures, myelosuppression, and renal failure. In the United States, the estimated annual
diagnosed incidence is 20 000, with a prevalence of approximately
62 000 as of 2007.2,3 MM accounts for 15% of all hematologic
malignancies and 2% of all malignancies.4 Advances in high-dose
chemotherapy and stem cell transplantation have improved overall
survival (OS) and event-free disease periods in MM,5-7 although
relapses are inevitable. Newer therapeutic agents, such as bortezomib, thalidomide, and lenalidomide, have demonstrated clinical benefit in patients with newly diagnosed8-13 and relapsed or
refractory disease.5,14,15 Despite these therapeutic advances, longterm control of relapsed/refractory MM remains elusive for most
patients. Progressive disease that is resistant to both immunomodulatory drugs and bortezomib is associated with a particularly poor
prognosis.16 As such, there remains an important need for additional novel therapies to augment existing first-generation agents
and continue to improve patient outcome.
Elotuzumab is a humanized monoclonal IgG1 antibody directed
against human CS1 (also known as CD2 subset-1, SLAMF7,
CRACC, and CD319), a cell surface antigen glycoprotein that is
highly expressed on MM cells and normal plasma cells. CS1 is
expressed at a lower level on natural killer (NK) cells, NK-like
T (NKT) cells, and a subset of CD8 positive T cells. Little to no
expression is detected on resting B cells, monocytes, CD4⫹ T cells,
granulocytes, hematopoietic stem cells, and epithelia, vessels, or
smooth muscle cells of all tissues.17
Elotuzumab has significant in vivo antitumor efficacy in
severe-combined immunodeficient (SCID) mice MM xenograft
models.17-19 Data obtained from these models and in vitro studies
using human peripheral blood mononuclear cells formed the basis
for the selection of the doses and schedule used in the current study.
This study was conducted to determine the maximum tolerated
dose of elotuzumab up to a maximum planned dose (MPD) of
20 mg/kg when given as a monotherapy and to characterize the
safety, pharmacokinetics (PK), and preliminary efficacy in adults
with advanced MM and limited treatment options.
Submitted June 20, 2011; accepted November 25, 2011. Prepublished online
as Blood First Edition paper, December 19, 2011; DOI 10.1182/blood-2011-06360552.
payment. Therefore, and solely to indicate this fact, this article is hereby
marked ‘‘advertisement’’ in accordance with 18 USC section 1734.
The publication costs of this article were defrayed in part by page charge
© 2012 by The American Society of Hematology
552
Methods
Study design
This was a multicenter, open-label, dose-escalation phase 1 study designed
to evaluate elotuzumab administered by intravenous infusion at up to 6 dose
levels (0.5, 1.0, 2.5, 5.0, 10, or 20 mg/kg) in patients with advanced MM.
Patients received elotuzumab once every 14 days for 8 weeks. Patients who
did not show evidence of progressive disease (PD) or relapse at week 8 had
BLOOD, 19 JULY 2012 䡠 VOLUME 120, NUMBER 3
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BLOOD, 19 JULY 2012 䡠 VOLUME 120, NUMBER 3
the option of receiving a second 8-week treatment course at the same dose
level and schedule. After completion of treatment, patients were evaluated
for adverse events (AEs) at 30 days and 60 days after last elotuzumab dose.
The study used a 3 ⫹ 3 dose escalation approach with each cohort starting
with 3 patients. For the first cohort, there was a 14-day observation period
between the first doses administered to each of the initial 3 patients
enrolled. Patients in subsequent dose cohorts could be dosed simultaneously. If no dose-limiting toxicity (DLT) was observed within the initial
28-day dosing period, enrollment commenced at the next higher dose level,
to an MPD of 20 mg/kg. If 1 patient in the cohort had a DLT, 3 additional
patients were enrolled in the cohort. If no additional DLT occurred, patient
enrollment to the next dose level proceeded. If a second patient in a cohort
had a DLT, study treatment in that cohort was to be stopped. An independent
Data Safety Monitoring Board reviewed the safety data for each cohort
before patients being enrolled into the next cohort. DLT was defined as any
grade 3 or greater elotuzumab-related AE (National Cancer Institute
Common Terminology Criteria for Adverse Events Version 3) occurring
during the first 28 days of therapy.
Elotuzumab was prepared according to protocol specifications and
infused at a rate of 2 mL/min with calibrated infusion pumps. Originally,
pretreatment with an antihistamine and acetaminophen was optional in
patients who experienced any infusion reaction. After the observation of
infusion-related AEs, the protocol was amended to require that all patients
receive an antihistamine and acetaminophen before and during each
infusion. In addition, unless contraindicated, an intravenous corticosteroid
was required to be administered before the first dose in 20 mg/kg
elotuzumab cohort.
The study was conducted in compliance with principles of the
International Conference on Harmonisation guidelines on Good Clinical
Practice, the Declaration of Helsinki, and the applicable local and national
regulations. All patients provided written informed consent.
The sponsor conducted the statistical analysis. Laboratory tests were
conducted at 3 central laboratories (CRL Medinet Inc, Mayo Laboratories,
and Esoterix Inc). In addition, PK and immunogenicity tests were conducted by the sponsor.
Patients were monitored for safety by assessing all AEs according to the
National Cancer Institute Common Terminology Criteria for Adverse
Events Version 3.0 until 60 days after the last dose of elotuzumab. Other
safety evaluations included complete blood count and serum chemistries,
vital signs, laboratory tests, chest x-ray, electrocardiogram, physical
examinations, Eastern Cooperative Oncology Group (ECOG) performance
status assessment, urinalysis, prothrombin time/partial prothromboplastin
time, 2-dimensional echocardiogram, skeletal survey, and bone marrow
aspirate or biopsy. Safety data were monitored on an ongoing basis by an
independent Data Safety Monitoring Board.
Treatment responses were determined by the investigator using the
European Group for Blood and Marrow Transplantation (EBMT) myeloma
response criteria,20 which included measurements of MM plasma cell levels
in the bone marrow, serum and urine M-protein, and serum and urinary free
light chain. Patients were evaluated for disease activity and survival up to
6 months after their last dose.
PK
Blood samples were collected throughout the study and until 60 days after
dose for the determination of PK parameters. Serum concentrations of
elotuzumab were assessed by an ELISA (assay range, 75-2000 ng/mL). PK
parameters, such as maximum serum concentration (Cmax), terminal phase
half-life (T1/2␭), systemic clearance (CL), area under the concentration-time
curve (AUC) from time zero to infinity (AUCinf), and AUC for the dosing
interval (AUC␶), were estimated using noncompartmental methods in
Phoenix WinNonlin Version 6.0 (Pharsight Corporation) using the constant
intravascular infusion model (model 202).
Immunogenicity
Immunogenicity testing was performed on samples collected up to 60 days
after treatment using a tiered approach. All samples were initially screened
for the presence of antibodies to elotuzumab (antidrug antibody [ADA])
ELOTUZUMAB MONOTHERAPY IN ADVANCED MM
553
using an electrochemiluminescent bridging assay. The screening assay
cut-point21 was set using baseline samples from patients in the study and
additional drug-naive MM serum. Screen-positive samples were titered and
then tested in a confirmatory assay by preincubating with soluble, excess
elotuzumab to determine whether a significant decrease in signal was
observed. Confirmed positive samples were then tested in a cell-based
neutralizing antibody (NAb) assay. The NAb assay format uses ruthenium
labeled elotuzumab that binds CS1 on cells in the presence of patient’s
baseline serum; if NAbs are present at later time points, a percentage
inhibition in signal relative to the baseline response can be observed. A
sample was considered NAb-positive when the relative percentage inhibition was greater than or equal to 17.41% (cut-off based on the variation
observed in the assay during validation).
Pharmacodynamics
CS1 saturation assays and lymphocyte counts. Whole blood and bone
marrow samples collected from patients at protocol-defined time points
were shipped by overnight courier to Esoterix Clinical Trial Services.
Percentage and absolute numbers of peripheral blood T, B, and NK cells
were analyzed using the BD TruCOUNT assay (BD Biosciences). CS1
saturation was measured using fluorescently labeled elotuzumab in a flow
cytometric assay. CS1 expression was assessed using a fluorescently
labeled monoclonal antibody that does not compete with elotuzumab for
binding to CS1. CS1 saturation and expression assays were performed on
peripheral NK and CD8⫹ T cells and on bone marrow NK cells, as well as
CD38⫹ and CD138⫹ putative myeloma cells.
Cytokines. Serum levels of interferon-inducible protein 10 (IP-10), a
chemokine that stimulates migration of activated T cells and NK cells, were
measured in a multiplexed assay using LINCO kits on the Luminex
platform (Linco Research). Samples were collected on the same day before
elotuzumab treatment and at 2 and 4 hours after elotuzumab dosing, and
then frozen until the assay was performed.
Statistical methods
The primary objective of the study was to evaluate the safety and identify
the maximum tolerated dose of elotuzumab, to an MPD of 20 mg/kg, in
patients with advanced MM. Secondary objectives were to evaluate the PK,
immunogenicity, and objective response rates determined by the EBMT
criteria. Exploratory objectives included: evaluations of CS1 expression on
bone marrow MM cells and peripheral NK, NKT, and CD8⫹ T cells; and
evaluation of biomarkers, including prognostic factors, such as serum
␤2-microglobulin (␤2M) and serum albumin.
The modified intent-to-treat population was defined as patients who
have received at least 1 dose of study medication. A patient was considered
DLT evaluable if the patient had received 2 doses of study medication or
had experienced a DLT resulting from the first treatment.
Patient eligibility
Patients eligible for the study included adults 18 years of age or older who
had a diagnosis of advanced MM and prior treatment with at least 2 prior
MM therapies. Patients were also required to meet the following criteria:
ECOG performance status score of 0 to 2; measurable M component in
serum (ⱖ 0.5 g/dL) and/or urine (ⱖ 0.2 g excreted in a 24-hour collection
sample); adequate bone marrow function (defined as absolute neutrophil
count ⬎ 1000 cells/mm3, platelets ⱖ 75 000 cells/mm3, and hemoglobin ⱖ 8 g/dL); serum calcium (corrected for albumin) level within normal
range; left ventricular ejection fraction more than or equal to 45%
(2-dimensional echocardiogram or multiple-gated acquisition scan within
30 days before first dose of study drug); negative pregnancy test within
48 hours before first dose in women of childbearing potential; serum
alanine aminotransferase or aspartate aminotransferase ⱕ 3⫻ the upper
limit of normal, total bilirubin ⱕ 2⫻ the upper limit of normal (unless
related to MM); and serum creatinine ⱕ 2.0 mg/dL (unless related to MM,
then ⱕ 3.0 mg/dL).
Patients were ineligible for this study if they had met any 1 of the
following criteria: life expectancy of less than 3 months; prior malignancy
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554
BLOOD, 19 JULY 2012 䡠 VOLUME 120, NUMBER 3
ZONDER et al
Table 1. Patient disposition (ITT population: total N ⴝ 35)
No. (%)
Received study drug
34 (97.1)
Completed initial treatment phase
25 (71.4)
Received re-treatment
Completed follow-up period
Completed treatment
8 (22.9)
16 (45.7)
6 (17)
Disease progression
Demographic/characteristic
Median age, y (range)
Value
64.5 (46-87)
Race, n (%)
Asian
2 (5.9)
Black of African heritage
3 (8.8)
White
Reasons for discontinuation
AE
Table 2. Patient demographics and baseline disease characteristics
(MITT population: total N ⴝ 34)
29 (85.3)
1 (2.9)
Sex, n (%)
20 (57.1)
Male
17 (50.0)
Female
17 (50.0)
DLT
2 (5.7)
Investigator’s decision
2 (5.7)
Patient’s decision
2 (5.7)
0
14 (41.2)
Other
2 (5.7)
1
13 (38.2)
2
6 (17.6)
3
0
ITT indicates intent to treat.
ECOG status, n (%)
4
(except for adequately treated basal cell or squamous cell skin cancer, in
situ cervical cancer, or other cancer from which the patient had been
disease-free for at least 5 years); plasma cell leukemia (active or prior);
uncontrolled medical problems, such as diabetes mellitus, coronary artery
disease, hypertension, unstable angina, arrhythmias, and pulmonary, hepatic, and renal diseases, unless renal insufficiency was thought to be
secondary to MM; solitary bone or solitary extramedullary plasmacytoma
as the only evidence of plasma cell dyscrasia; corticosteroid, bortezomib, or
other proteasome inhibitor, thalidomide, lenalidomide, or melphalan within
2 weeks of the first dose of elotuzumab; nitrogen mustard agents within
6 weeks of the first dose of elotuzumab; investigational drug within 4 weeks
or 5 half-lives (whichever was greater) of the first dose of elotuzumab; stem
cell or bone marrow transplant within 12 weeks before the first dose of
elotuzumab; biologic agents, including intravenous immunoglobulin and
monoclonal antibodies within 4 weeks of the first dose of elotuzumab;
neuropathy more than grade 2; symptomatic orthostatic hypotension;
evidence of amyloidosis; known active infections requiring antibiotics,
antivirals, or antifungals; serious psychiatric illness, active alcoholism, or
drug addiction that may hinder or confuse follow-up evaluation; hypersensitivity to recombinant proteins or excipients in the investigational agent;
platelet transfusion within 72 hours of obtaining screening platelet count;
and any condition that in the investigator’s opinion made the patient
unsuitable for study participation.
To mitigate infusion reactions, the original protocol was amended to
include a premedication regimen; patients in the 20-mg/kg elotuzumab
cohort received premedication of 50 mg methylprednisolone, diphenhydramine, and acetaminophen before the first elotuzumab dose only. Diphenhydramine and acetaminophen were suggested before each subsequent
infusion. Another amendment allowed patients who demonstrated stable
disease or better at day 56 to receive additional doses of elotuzumab.
Results
Study population
The study was conducted between November 2006 and August
2009 at 8 sites in the United States and 1 in France. Study
disposition is detailed in Table 1. Fifty-one patients were screened,
of which 35 were enrolled into 6 dosing cohorts: 3 in the 0.5-mg/kg
cohort, 4 in the 1.0-mg/kg cohort, 6 in the 2.5-mg/kg cohort, 4 in
the 5.0-mg/kg cohort, 4 in the 10-mg/kg cohort, and 14 in the
20-mg/kg cohort. Thirty-four patients received study treatment.
One patient was enrolled in the 10-mg/kg cohort but was withdrawn from the study by the investigator before receiving study
medication after developing severe neuropathy. One patient each in
the 1.0-mg/kg and 5.0-mg/kg cohorts withdrew from the study
because of disease progression after receiving one or 2 doses. In
each of these 3 cohorts, another patient was enrolled as a
replacement.
1 (2.9)
Median time since first diagnosis, y (range)
4.4 (0.9-12.8)
Prior multiple myeloma treatments
Median no., (range)
4.5 (2-10)
Lenalidomide, n (%)
28 (82.4)
Thalidomide, n (%)
27 (79.4)
Bortezomib, n (%)
28 (82.4)
MITT indicates modified intent to treat.
Patient demographics and disease characteristics are presented
in Table 2. Most patients were white, with a median age of
64.5 years and a median of 4.5 prior MM treatments. All patients
had received prior immunomodulatory agents; 28 (82.4%) and
27 (79.4%) had received lenalidomide and thalidomide, respectively. Twenty-eight (82.4%) patients had received prior bortezomib.
Of the 34 patients treated, 25 completed the initial treatment
phase and 8 were subsequently retreated. A median of 4 infusions
were administered (range, 1-12). Reasons for treatment cessation
are detailed in Table 1. The majority of patients discontinued
treatment because of disease progression. In addition to the
2 patients who discontinued treatment because of DLTs (detailed in
“AEs”), 1 patient in the 0.5-mg/kg cohort discontinued because of
unrelated AEs of headache and congestive cardiac failure, which
required hospitalization. Sixteen patients completed the 6-month
posttreatment follow-up period.
Safety
Two patients experienced DLTs during their first cycle of treatment:
1 patient in the 2.5-mg/kg cohort had an episode of grade 3
increased serum creatinine, and 1 patient in the 20-mg/kg cohort
Table 3. Treatment-related AEs in more than 5% of patients overall
(MITT population: total N ⴝ 34)
AEs
No. (%)
No. with any treatment-related AEs
18 (52.9)
Chills
11 (32.4)
Pyrexia
6 (17.6)
Flushing
4 (11.8)
Chest discomfort
3 (8.8)
Fatigue
3 (8.8)
Headache
3 (8.8)
Sinus tachycardia
3 (8.8)
Vomiting
3 (8.8)
Anorexia
2 (5.9)
Dyspnea
2 (5.9)
Serum creatinine increased
2 (5.9)
MITT indicates modified intent to treat.
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BLOOD, 19 JULY 2012 䡠 VOLUME 120, NUMBER 3
ELOTUZUMAB MONOTHERAPY IN ADVANCED MM
555
Table 4. PK parameters for the first and fourth doses of elotuzumab*
Dose,
mg/kg
Dose
T1/2␭,
days†
Tmax, hr
Cmax, mcg/mL‡
Vz, mL†
CL, mL/hr†
AUC␶, mcg*hr/mL
AUCinf, mcg*hr/mL
1
2.1 ⫾ 0.5
1.9 ⫾ 1.0
11.3 ⫾ 3.0
4291.2 ⫾ 852.5
71.4 ⫾ 19.9
596.8 ⫾ 151.5
634.1 ⫾ 144.9
4
NA
3.2 ⫾ 2.8
7.5 ⫾ 2.5
NA
NA
NA
NA
1.0
1
3.2 ⫾ 0.6
1.5 ⫾ 0.0
17.6 ⫾ 4.8
6194.8 ⫾ 2477.9
65.2 ⫾ 16.7
2328.2 ⫾ 1413.7
1342.6 ⫾ 387.0
4
NA
2.0 ⫾ 0.8
25.7 ⫾ 19.9
NA
NA
5777.5 ⫾ 6395.8
1322.0 ⫾ NA
2.5
1
4.4 ⫾ 1.8
2.8 ⫾ 0.9
45.2 ⫾ 12.1
4656.3 ⫾ 1932.8
40.4 ⫾ 28.3
5319.5 ⫾ 2892.3
6337.4 ⫾ 3911.5
4
NA
3.5 ⫾ 2.3
37.6 ⫾ 24.9
NA
NA
5.0
1
6.6 ⫾ NA
4.4 ⫾ 1.7
90.5 ⫾ 27.1
4757.7 ⫾ 240.9
22.1 ⫾ NA
4
NA
4.2 ⫾ 2.1
160.7 ⫾ 58.9
NA
NA
10
1
4.6 ⫾ 0.1
4.2 ⫾ 2.4
337.4 ⫾ 65.8
2976.9 ⫾ 366.5
15.3 ⫾ 8.6
4
NA
4.8 ⫾ 1.4
216.6 ⫾ 37.2
NA
NA
26 506.4 ⫾ NA
27 220.0 ⫾ NA
20
1
7.8 ⫾ 0.3
6.8 ⫾ 6.4
415.3 ⫾ 90.0
4781.6 ⫾ 1482.8
15.7 ⫾ 4.9
74 850.6 ⫾ 17 969.5
86 152.6 ⫾ 26 732.0
4
NA
4.2 ⫾ 1.4
563.0 ⫾ 112.5
NA
NA
162 390.2 ⫾ 89 871.7
NA
0.5
5508.9 ⫾ NA
14 403.9 ⫾ 4086.1
5884.2 ⫾ 511.9
13 718.0 ⫾ NA
46 420.5 ⫾ NA
14 172.8 ⫾ NA
40 544.4 ⫾ 28 741.7
28 378.2 ⫾ 12 432.9
Data are mean ⫾ SD.
VZ indicates volume of distribution; and NA, not applicable.
*Patients with positive immunogenicity response were excluded from these PK analyses.
†Parameter estimation for the fourth dose was excluded as the steady-state concentration was not achieved or data were insufficient for the estimation.
‡Observed data.
experienced a grade 3 hypersensitivity reaction that resolved
spontaneously within 24 hours. Subsequently, both patients discontinued study treatment. As a consequence, the 2.5-mg/kg cohort
was expanded to 6 patients. A maximum tolerated dose was not
reached in this study up to the MPD of 20 mg/kg.
AEs
Overall, 30 patients (88.2%) reported treatment-emergent AEs. The
most frequent treatment-emergent AEs, regardless of attribution to
study medication, included chills, fatigue, pyrexia, cough, headache, anemia, nausea, and back pain. Most events were grade 1 or
2 in severity. Eighteen patients (52.9%) experienced AEs attributed
to elotuzumab. Table 3 details the most frequent treatment-related
AEs. Thirty-one serious AEs were reported in 15 patients (44.1%).
Six serious AEs occurring in 4 patients were assessed as related to
treatment with elotuzumab: bradycardia (grade 2), chest discomfort
(grade 2), chills (grade 2), hypersensitivity (grade 3), pyrexia
(grade 2), and acute renal failure (grade 4), which was treated with
medications, resolved to grade 3 at 5 days later, and required
dialysis after the patient’s discharge from the hospital.
Overall, there were 10 (29.4%) patients who developed an
infection during the course of therapy, including 7 patients who had
grade 3 or 4 infections assessed as unrelated to elotuzumab. There
were no opportunistic viral or fungal infections. The analysis of
infection AEs and serious AEs did not reveal a dose-dependent
relationship to elotuzumab.
Four patients died during the course of the study. One patient
died of renal failure 20 days after the last elotuzumab dose and
13 days after discontinuation from study because of disease progression.
Three patients died because of disease progression. The events
leading to death were assessed as not related to study drug.
Before the implementation of the revised infusion management
guidelines, 13 of 25 treated patients experienced infusion reactions,
which with one exception (grade 3 hypersensitivity reaction) were
grade 1 or 2 in severity. In total, 5 patients had at least one infusion
interrupted, discontinued, or rate of infusion reduced in response to
an infusion reaction. Most frequent infusion reactions presented as
chills, pyrexia, headache, and flushing. Twenty (58.8%) patients
reported an infusion reaction during the first elotuzumab infusion.
However, 10 patients had reactions at subsequent infusions.
Following a protocol amendment to require infusion reaction
premedication immediately before a first dose of elotuzumab, no
further serious or grade 3 and 4 infusion reactions were observed.
Grade 1 and 2 infusion reactions either resolved spontaneously,
typically within 24 hours, or were managed as clinically indicated.
Efficacy
Response. Overall, no objective responses were observed during
the course of the study while patients were receiving treatment. Using the EBMT myeloma response criteria, 9 patients
(26.5%) were classified as having stable disease; the remaining
patients had PD.
PK, pharmacodynamics, and immunogenicity
PK parameters after the first and fourth doses are summarized in
Table 4. Observed mean drug concentration versus time profiles for
all dose groups are shown in Figure 1.
After administration of the first dose, Cmax increased in a
dose-proportional manner across the dose range of 0.5 mg/kg to
20 mg/kg; however, mean estimates of AUC and AUCinf increased
greater than proportionally, suggesting nonlinear PK. The mean
clearance decreased and mean T1/2␭ increased with an increase in
dose from 0.5 mg/kg to 20 mg/kg after first dose administered,
indicating a saturation of target-mediated elimination. The volume
of distribution was consistent across doses and approximated
serum volume.
Saturation of CS1 by elotuzumab on bone marrow target cells
increased as the dose of elotuzumab increased. At doses of
10 mg/kg and 20 mg/kg elotuzumab, CS1 receptors on bone
marrow–derived myeloma cells were consistently saturated. Lower
dose groups exhibited more variation in the level of target cell
saturation achieved (Figure 2).
Table 5 summarizes the incidence of positive results to immunogenicity assays. Overall, 31 patients were tested for immunogenicity; of these, 12 of 31 (39%) were positive for ADAs, and 11 of
12 of these ADA-positive samples were also NAb-positive. The
incidence of immunogenicity varied across dose groups (Table 5).
Fewer positive responses (3 of 16) were observed for patients in the
higher dose groups of 10 mg/kg and 20 mg/kg compared with the
lower dose groups (9 of 15). PK analysis suggested that ADA
responses seen at lower doses had a more noticeable impact on PK
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BLOOD, 19 JULY 2012 䡠 VOLUME 120, NUMBER 3
ZONDER et al
First Dose
1000
100
10
1
0.1
LLOQ=0.075 µg/mL
0.01
0
7
14
Serum Concentration
of Elotuzumab (µg/mL)
Serum Concentration
of Elotuzumab (µg/mL)
556
1000
100
10
1
0.1
0.01
0.001
0.5 mg/kg (n=3)
1.0 mg/kg (n=4)
2.5 mg/kg (n=6)
5.0 mg/kg (n=4)
10 mg/kg (n=3)
20 mg/kg (n=14)
LLOQ=0.075 µg/mL
Dosing
0
28
56
than those seen at higher doses. In the patients with a positive ADA
response in the lower dose groups (ⱕ 5 mg/kg), serum trough
concentrations were lower compared with those who had no ADA
response. ADA responses were minimized at the 10-mg/kg and
20-mg/kg doses and CS1 receptors on the target cells were
saturated, even when an NAb response was positive. There was no
correlation between positive ADA results and AEs, response, or
disease progression.
Transient decreases in absolute lymphocyte counts were observed after the first elotuzumab infusion (Figure 3). The transient
decrease included both CS1⫹ (NK cells and CD8⫹ T cells) and
CS1⫺ (CD4⫹ T cells and B cells) cell subsets, and cell counts
subsequently returned to near baseline levels by day 7 of follow-up.
This transient reduction in cell counts after the initial dose was
associated with a transient increase in IP-10, a chemokine that
stimulates migration of activated T cells and NK cells (Figure 4).
This suggests that lymphocyte cell trafficking out of the periphery
after dosing with elotuzumab was responsible for the decrease
observed. There was no evidence of lymphocyte depletion associated with repeated dosing of elotuzumab.
Discussion
% Occupancy of CS1 by Elotuzumab
on CD45dim CD38+ BM Cells
(at Day 56)
Despite success in lymphoma22,23 and leukemia,24,25 effective
monoclonal antibody therapy for patients with MM has been
elusive to date.26 The earliest trials of monoclonal antibodies in
MM involving the anti-CD20 antibody rituximab yielded disappointing results,27 possibly because of relatively low target antigen
expression on myeloma cells, or impaired complement-dependent
95% Emax
80
0.5 mg/kg
1.0 mg/kg
2.5 mg/kg
5.0 mg/kg
10 mg/kg
20 mg/kg
60
40
20
and/or antibody-dependent cellular cytotoxicity (ADCC) in myeloma patients.28 Impaired immunity may also explain the limited
success achieved with 2 separate anti-CD40 antibodies (dacetuzumab [SGN-40] and lucatumumab [CHIR12䡠12, HCD122]) despite more robust target antigen expression.29-31 Monoclonal antibodies directed against other targets relevant to the treatment of
MM, including CD56,32 CD38,33 CD138,34 RANKL,35 IL-6,36 and
CS1 (described herein) are currently in development.
This study demonstrated that elotuzumab was generally well
tolerated at doses sufficient to achieve biologically relevant serum
levels and near-complete saturation of the glycoprotein target CS1.
Dosing at either 10 mg/kg or 20 mg/kg resulted in target saturation
(ⱖ 95% of CS1 receptors) without dose-limiting toxicity.
With the exception of 1 case of acute renal failure that was
attributed to elotuzumab, the treatment-related toxicity observed
was largely limited to grade 1 and 2 infusion reactions that usually
occurred with the first infusion of elotuzumab, and typically
resolved within 24 hours either spontaneously or with treatment as
indicated. Infusion reactions are a common side effect of monoclonal antibody therapy. Of note, no grade 3 or 4 and serious
elotuzumab-associated infusion reactions were observed after the
introduction of a premedication regimen. A refined premedication
regimen for prevention of infusion reactions is being tested in
subsequent phase 2 and 3 elotuzumab trials.
Although the one case of severe renal impairment was thought
to be related to elotuzumab by the treating physician, it is unclear
what the mechanism for this might be because CS1 is not
detectable in the kidney and elotuzumab is not cleared through the
kidney.
As expected based on the lack of tissue expression of CS1,
neutropenia and thrombocytopenia were not observed. Infection
assessment was of interest in this study because elotuzumab
showed transient decreases in the count of several T-cell subsets.
There did not appear to be any evidence of chronic depletion of
T cells (data not shown). Although there were 7 grade 3 or
4 infections, there did not appear to be a relationship to the dose of
elotuzumab. Most infections tended to be bacterial in nature and
Table 5. Incidence of immunogenicity (patients positive for antidrug
antibodies and neutralizing antibodies)
Dose,
mg/kg
0
0.01
84
Time (Day)
Time (Day)
100
0.1
Figure 1. Observed elotuzumab serum concentration
versus time curves (mean ⴞ SD). LLOQ indicates lower
limit of quantification; and SD, standard deviation.
First Treatment Cycle
and Follow-up
1
10
100
1000
10000
Serum Concentration of Elotuzumab
(µg/mL)
Figure 2. CS1 saturation of bone marrow CD38ⴙ cells at day 56. Symbols indicate
observed data from individual patients at each dose level. The vertical line indicates
target level of serum elotuzumab concentration (70 ␮g/mL) based on preclinical
studies. BM indicates bone marrow; and Emax, maximum effect.
No.
Confirmed* ADA-positive patients
NAb-positive patients
0.5
3
3
2
1.0
4
1
1
2.5
5
3
3
5.0
3
2
2
10
3
1
1
20
13
2
2
*Patients having at least 1 postdose sample available for analysis.
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BLOOD, 19 JULY 2012 䡠 VOLUME 120, NUMBER 3
ELOTUZUMAB MONOTHERAPY IN ADVANCED MM
A
Mean Lymphocyte Counts (Cells/mm3)
Figure 3. Transient decrease in lymphocyte counts. N ⫽ number of
patients at baseline. Changes in cell count (from baseline to 2 hours after
first dose, and from 2 hours after first dose to day 56) were significant for
both (A) total lymphocyte counts (P ⫽ .002 and .004, respectively) and
(B) NK cell counts (P ⫽ .0025 and .032, respectively). *Postdose. All other
assessments were performed predose.
557
0.5 mg/kg (n=3)
1.0 mg/kg (n=2)
2.5 mg/kg (n=6)
5.0 mg/kg (n=4)
10 mg/kg (n=3)
20 mg/kg (n=14)
Dosing
2300
1900
Mean for healthy patients
1500
1100
700
300
-100
Scn
0
0*
0*
(2 hr) (4 hr)
2
7
14
21
28
35 42
42* 42*
(2 hr) (4 hr)
49
52
56
Time (Day)
B
0.5 mg/kg (n=3)
1.0 mg/kg (n=2)
2.5 mg/kg (n=6)
5.0 mg/kg (n=4)
10 mg/kg (n=3)
20 mg/kg (n=14)
Mean NK Counts (Cells/mm3)
Dosing
400
300
Mean for healthy patients
200
100
0
-100
Scn
0
0*
0*
(2 hr) (4 hr)
2
7
14
21
28
35 42
42* 42*
(2 hr) (4 hr)
49
52
56
Time (Day)
recovered with standard of care treatment. No evidence of opportunistic infections was observed.
No objective myeloma responses were seen in this heavily
pretreated patient population, despite plasma cell target saturation
at the higher elotuzumab doses studied. In preclinical models,
elotuzumab exerted its anti-myeloma effect primarily via NK
cell–mediated ADCC.17 It is conceivable that less-heavily pretreated patients would have better NK cell function, possibly
resulting in a more robust ADCC response.37
Both bortezomib and lenalidomide have been shown to
enhance elotuzumab-mediated antimyeloma activity in preclinical models.18,19,38 Given this effect and the nonoverlapping
toxicity of elotuzumab with either of these agents, there is a
strong rationale for exploring combination therapy. Clinical
trials combining elotuzumab at doses of 10 mg/kg and 20 mg/kg
Concentration (pg/mL)
15000
1st Dose
2nd Dose
3rd Dose
with each of these drugs are being conducted and have shown
evidence of activity.39-41
Acknowledgments
The authors thank the research nurses, physicians, coordinators,
and other staff at the study sites; Dr Mohamad A. Hussein for his
contributions to the design and execution of this study; Dr Ted
Everson, AOI Communications LP, for medical writing assistance in the
preparation of this manuscript; and the patients and their families.
This work was supported by Bristol-Myers Squibb. AOI
Communications LP provided medical writing, editorial support,
and graphics assistance.
4th Dose
10000
5000
0
0
0*
0*
(2 hr) (4 hr)
1
2
7
14
14* 14* 28 28* 28* 42 42* 42* 43
(2 hr) (4 hr)
(2 hr) (4 hr)
(2 hr) (4 hr)
Time (Day)
56
Figure 4. Individual patient serum IP-10 levels (20-mg/kg cohort,
n ⴝ 6). *Postdose. All other assessments were performed predose.
From www.bloodjournal.org by guest on April 29, 2017. For personal use only.
558
BLOOD, 19 JULY 2012 䡠 VOLUME 120, NUMBER 3
ZONDER et al
Authorship
Contribution: J.A.Z. was a co-investigator for this study, acquired,
analyzed, and interpreted data, and drafted, revised, and gave final
approval of the manuscript; A.F.M. enrolled subjects, reviewed and
corrected data, and revised and interpreted the manuscript; S.S.
treated patients and developed and gave final approval of the
manuscript; F.v.R. acquired data and drafted and gave final
approval of the manuscript; W.I.B. designed the study, analyzed
data, and reviewed and gave final approval of the manuscript; H.D.
performed the PK and pharmacodynamics analysis for the study,
interpreted data, and provided PK/PD figures for the manuscript;
J.F. designed the study, analyzed data, and drafted the manuscript;
D.E.H.A. designed the clinical study and pharmacodynamic work,
and interpreted the PK/pharmacodynamics relationship; and A.K.S.
designed and executed the study, including preliminary review of
data, and assisted with the preparation and gave final approval of
the manuscript.
Conflict-of-interest disclosure: A.F.M. is on the Speakers’
Bureau of Genentech Inc, Celgene Corporation, and Millennium
Pharmaceuticals Inc. S.S. is on the Speakers’ Bureau of Celgene
Corporation and Millennium Pharmaceuticals Inc. F.v.R. has
received research funding for medical sciences from the University
of Arkansas and funding for laboratory research from Facet Biotech
(now Abbott Biotherapeutics Corp). W.I.B. has received research
funding from PDL Biopharma Inc. H.D. is an employee of Abbott
Biotherapeutics Corp (formerly Facet Biotech). J.F. is a former
employee of and has previously held stock in Facet Biotech (now
Abbott Biotherapeutics Corp). D.E.H.A. is a former employee of
Facet Biotech (now Abbott Biotherapeutics Corp). A.K.S. is an
employee of Abbott Biotherapeutics Corp (formerly Facet Biotech). J.A.Z. has received speaker honoraria from Celgene Corporation and research funding from Millennium.
Correspondence: Jeffrey A. Zonder, Department of Oncology,
Karmanos Cancer Institute, Wayne State University School of
Medicine, 4100 John R St, Detroit, MI 48201; e-mail:
[email protected].
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2012 120: 552-559
doi:10.1182/blood-2011-06-360552 originally published
online December 19, 2011
A phase 1, multicenter, open-label, dose escalation study of elotuzumab
in patients with advanced multiple myeloma
Jeffrey A. Zonder, Ann F. Mohrbacher, Seema Singhal, Frits van Rhee, William I. Bensinger, Han
Ding, John Fry, Daniel E. H. Afar and Anil K. Singhal
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