1
A Phase 2 Multicenter Study of
CNTO 328, an AntiInterleukin-6
Monoclonal Antibody, in Patients
With Relapsed or Refractory
Multiple Myeloma
P.M. Voorhees, R.F. Manges, G. Somlo,
S. Lentzsch, S. Jagannath, P. Sonneveld,
R.C. Frank, S. Zweegman,
P.W. Wijermans, B. Rijnbeek, Q. Xiang,
H. Xie, S. Thomas
2
Introduction
ˇ Patients with relapsed and refractory multiple
myeloma (MM) are in urgent need of effective and
well-tolerated treatment regimens
ˇ High-dose glucocorticoids (GCs) are a well-
established treatment for MM and continue to be
an important component of therapeutic regimens
ˇ Resistance to GCs is common; therefore, new
therapies that target known mechanisms of GC
resistance may enhance the efficacy of this class
of agents in the treatment of MM
3
Introduction (cont)
ˇ In preclinical models, interleukin (IL)-6 has
been shown to
Promote the proliferation and survival of
MM cells1,2
Protect MM cells from GC-induced apoptosis3,4
Act as an important GC resistance factor in
the bone marrow microenvironment5
ˇ Blocking IL-6 may augment the activity
of and restore sensitivity to GCs in MM
1. Bataille R, et al. Blood. 1995;86(2):685-691.
2. Kawano M, et al. Nature. 1988;332(6159):83-85.
3. Hardin J, et al. Blood. 1994;84(9):3063-3070.
4. Rowley M, et al. Blood. 2000;96(9):3175-3180.
5. Cheung WC, Van Ness B. Leukemia. 2001;15(2):264-271.
4
CNTO 328
ˇ CNTO 328 is a chimeric monoclonal antibody with
high affinity for human IL-6
ˇ In preclinical studies, CNTO 328 potentiated the
apoptotic activity of dexamethasone (Dex) in IL-6
dependent and independent human MM cell lines,
including a bortezomib-resistant cell line, in both
the presence and absence of bone marrow
stromal cells, as well as in plasma cells derived
from patients with MM1
ˇ CNTO 328 has a favorable safety profile that
allows for combination with high-dose GCs, even
in heavily pretreated MM
1. Voorhees PM, et al. Br J Haematol. doi:10.1111/j.1365-2141.2009.07647.x.
5
T05 Study Rationale1
IL-6 dependent
Bortezomib resistant
IL-6 independent
1. Voorhees PM, et al. Br J Haematol. doi:10.1111/j.1365-
*P < 0.01.
2141.2009.07647.x.
6
T05 Study Rationale1 (Cont)
Control mAb
CNTO 328
A.
B.
P <0.00001
P = 0.03
P = 0.0003
P <0.0001
P = 0.04
P = 0.004
120
120
)
)
% 100
% 100
(
(
80
80
60
60
viability
viability
40
40
Cell
Cell
20
20
0
0
EtOH
Dex
EtOH
Dex
10 M
1 M
ˇ (A) newly diagnosed multiple myeloma sample
ˇ (B) glucocorticoid-resistant plasma cell leukemia sample
1. Voorhees PM, et al. Br J Haematol. doi:10.1111/j.1365-
2141.2009.07647.x.
7
T05 Study Design
ˇ Single-arm, open label, multicenter, phase II trial in
relapsed OR refractory MM with 2 or more previous
lines that must have included bortezomib
Plan A: CNTO 328 single agent; Dex added if no response
Plan B: CNTO 328 and Dex given concurrently
ˇ Doses
CNTO 328 6 mg/kg/2 wk
Dex 40 mg/d 1-4, 9-12, 17-20
ˇ Primary endpoint: overall response
ˇ Secondary: TTP, DOR, safety, PK, IR, biomarkers
ˇ The current study combines patients treated with
both CNTO 328 and Dex from Plan A and B
8
T05 Study Design (Cont)
ˇ Key eligibility criteria
Measurable secretory disease
Relapsed/refractory disease, defined as
At least 2 prior lines of therapy
Prior treatment regimen must have included
bortezomib
Documented relapse or no response to last prior
therapy (according to European Group for Blood and
Marrow Transplantation [EBMT] criteria)
Adequate bone marrow, liver, and renal function
9
Patient Demographic and Clinical
Characteristics
Characteristic
(N = 45)
Median (range) age, y
65 (43-89)
Median (range) time since diagnosis, y
4.4 (1-13)
2M 3.5 mg/L, n (%)
28 (62)
Median (range) serum albumin, g/dL
3.7 (2.7-7.9)
Median (range) CRP, mg/L
1.7 (0.2-264)
Median (range) number of prior therapeutic lines
5 (2-9)
Received 3 prior lines, n (%)
33 (73)
Received 4 prior lines, n (%)
30 (67)
Received 5 prior lines, n (%)
26 (58)
2M, 2-microglobulin; CRP, C-reactive protein.
10
Treatment Responses
Median (range)
Best
Patients,
duration
response
n
of response, mo
Status
CR
0
PR =
PR
9a
5.5 (2.8-19.8)
3 still ongoing
20%
PR + MR =
MR
4b
3.2 (1.6-6.4)
30%
SD
23
3 still ongoing
PD
8c
CR, complete response; PR, partial response; MR, minimal response; SD, stable disease; PD, progressive disease.
aIncludes 1 patient with only a 4-week confirmation.
bIncludes 1 patient with only a 3-week confirmation.
cOne unconfirmed; patient discontinued study treatment because of toxicity.
11
Duration of Treatment Response*
*Data derived from all pts with PRs
12
Summary of Prior Therapies
All
PR + MR
(N = 45)
(n = 13)
Therapies prior to study entry, n (%)
Any proteasome inhibitora
45 (100)
13 (100)
Any corticosteroidb
41 (91)
13 (100)
Any alkylating agentc
38 (84)
11 (85)
Any IMiDd
37 (82)
11 (85)
Any anthracyclinee
28 (62)
9 (69)
Received 3 of the above, n (%)
42 (93)
13 (100)
Received 4 of the above, n (%)
35 (78)
12 (92)
Received 5 of the above, n (%)
22 (49)
6 (46)
Any prior stem cell transplant, n (%)
26 (58)
6 (46)
IMiD, immunomodulatory drug.
aIncluding bortezomib or carfilzomib.
bIncluding dexamethasone or prednisone.
cIncluding melphalan or cyclophosphamide.
dIncluding thalidomide or lenalidomide.
eIncluding doxorubicin alone or in combination (eg, VAD [vincristine, Adriamycin {doxorubicin}, dexamethasone] regimen).
13
Summary of Last Prior Therapy
All
PR
MR
PR + MR
(N = 45)
(n = 9)
(n = 4)
(n = 13)
Last therapy prior to study
entry, n (%)
Any proteasome inhibitor
25 (56)
7 (78)
1 (25)
8 (62)
Any corticosteroid
24 (53)
3 (33)
2 (50)
5 (38)
Any alkylating agent
8 (18)
0
1 (25)
1 (8)
Any IMiD
13 (29)
2 (22)
1 (25)
3 (23)
Any anthracycline
5 (11)
0
2 (50)
2 (15)
Evidence for refractory
disease, n (%)
28 (62)
5 (56)
2 (50)
7 (54)
PD on last prior therapy
14 (31)
3 (33)
1 (25)
4 (31)
Best response <PR
3 (7)
0
0
0
Response and relapse within
60 days
11 (24)
2 (22)
1 (25)
3 (23)
PR, partial response; MR, minimal response; IMiD, immunomodulatory drug; PD, progressive disease.
14
Impact of refractoriness to last prior
proteasome inhibitor- and/or IMiD-based
regimen
PR + MR,a n
Nonresponders, n
Refractory
5
17
Not refractory
6
6
IMiD, immunomodulatory drug; PR; partial response; MR, minimal response.
aP = 0.14 for patients who were refractory to their last prior therapy (ie,
proteasome inhibitor and/or IMiD) vs patients who were not refractory (Fisher
exact chi-square test).
15
Most Common AEs*
50
All Grades
Grades 3
40
33
Grades 4
atientsp 30
of
22
18
18
20
16
13
13
13
11
11
10
7
9
Percentage
4
4
0
222
0
00
000
000
000
0
usea
spnea
utropenia
Infections
Fatigue
Na
Ne
Thrombocytopenia
Anemia
Diarrhea Oral pain
Myalgia Dy
AE, adverse event; Dex, dexamethasone.
*Those occurring in >10% of pts reasonably related to CNTO 328 in combination with dex
16
Conclusions
ˇ CNTO 328 was well tolerated in combination
with Dex
ˇ Partial response rate 20%
PR+MR 30%
ˇ Partial responses were durable
Median duration of PR was 5.5 months (range, 2.8-
19.8 months)
All partial responders are still alive
ˇ Responses were seen in patients who had been
treated with at least 2 prior lines of therapy,
including those who were refractory to at least
1 of these prior treatment lines
17
Conclusions (cont)
ˇ The majority (85%) of patients with a PR or MR
received a proteasome inhibitor or immuno-
modulatory drug (IMiD) as their last prior therapy
Refractoriness to this last prior therapy did not have a
statistically significant impact on patient response to
CNTO 328 and Dex
ˇ CNTO 328 plus Dex is a promising new
combination for the treatment of relapsed and
refractory MM. Further studies evaluating CNTO
328 in combination with GC-based therapy are
warranted