Dacetuzumab (SGN-40), Lenalidomide, and Weekly Dexamethasone in Relapsed or Refractory Multiple Myeloma: Multiple Responses Observed in a Phase 1b Study
Edward Agura1, Ruben Niesvizky2, Jeffrey Matous3, Nikhil Munshi4, Mohamad Hussein5, Ramakrishnan V. Parameswaren6, Stefano Tarantolo7, Nancy C. Whiting8, Jonathan G. Drachman8, and Jeffrey A. Zonder9
1Baylor Sammons Cancer Center, Dallas TX; 2Weil Cornel Medical Col ege, New York NY; 3Rocky Mountain Cancer Center, Denver CO; 4Dana Farber Cancer Institute, Boston MA; 5H. Lee Moffitt Cancer Center, Tampa FL;
6Avera Cancer Institute, Sioux Falls SD; 7Estabrook Cancer Center, Omaha NE; 8Seattle Genetics, Inc, Bothell WA; 9Karmanos Cancer Institute, Detroit MI.
Dacetuzumab (SGN-40)
Cycle 1
intrapatient dose
Cycles 2-8
Safety
Serious Adverse Events
Subgroup Analyses
escalation
· Dacetuzumab is a humanized monoclonal antibody that targets
Antitumor
Antitumor
Adverse Events Occurring in >15% of Patients
· 6 (17%) patients with SAEs related to study treatment:
Best Percentage Change in M-Protein from
assessment
assessment
CD40, a type 1 transmembrane protein of the TNF receptor
Dacetuzumab
cohort-specific doses
SAEs related to dacetuzumab 3 (8%) patients:
Baseline by Prior Lenalidomide Exposure
superfamily
Cohort
Day
14 8
15
22
28
1
8
15
22a 28
abdominal pain, fatigue, hypoxia, nausea, acute renal
Dexamethasone 40 mg
·
·
M-protein reductions were similarly observed in both
CD40 is highly expressed on several types of B-cell hematologic
1
2
3
Expansion
Total
failure, tumor lysis syndrome, and vomiting
Lenalidomide 25 mg daily
Dacetuzumab dose level
4 mg/kg
8 mg/kg
12 mg/kg
12 mg/kg
(N=36)
lenalidomide-naive and lenalidomide-pretreated patients
malignancies, including multiple myeloma (MM)
Preferred terma
(N=6)
(N=3)
(N=6)
(N=21)
n (%)
SAEs related to lenalidomide 3 (8%) patients
a dacetuzumab dose deleted in Cycles 5-8
· In prior phase 1 studies of dacetuzumab monotherapy, antitumor
Fatigue
4 (67)
2 (67)
2 (33)
12 (57)
20 (56)
SAEs related to dexamethasone 4 (11%) patients
Lenalidomide-naive (N=18)
Lenalidomide-pretreated (N=18)
activity was demonstrated in patients with non-Hodgkin
Dacetuzumab cohort-specific doses (mg/kg)
Neutropenia
3 (50)
1 (33)
1 (17)
8 (38)
13 (36)
elin
lymphoma, and stabilization of disease was noted in MM patients
Cycle 1 Day 1
Cycle 1 Day 4
All subsequent doses
Thrombocytopenia
2 (33)
1 (33)
2 (33)
6 (29)
11 (31)
Cohort 1
2
2
4
base
· Preclinical data demonstrate that the addition of lenalidomide to
Cohort 2
4
4
8
Diarrhea
1 (17)
2 (67)
2 (33)
4 (19)
9 (25)
Efficacy
dacetuzumab markedly enhances dacetuzumab-mediated ADCC
Cohort 3
4
8
12
Arthralgia
2 (33)
1 (33)
0
5 (24)
8 (22)
from
and apoptosis in MM cell lines and patient isolates through
Constipation
0
2 (67)
1 (17)
5 (24)
8 (22)
Best Clinical Response
rFLC
increased NK cell activity
Dizziness
2 (33)
1 (33)
1 (17)
4 (19)
8 (22)
no
Patients
· Objective responses (CR+PR) were observed in all dose
Headache
1 (17)
1 (33)
1 (17)
5 (24)
8 (22)
otei
levels:
-pr
Nausea
1 (17)
0
3 (50)
4 (19)
8 (22)
Proposed Dacetuzumab Mechanism of Action
Key Inclusion Criteria
16/36 (44%) patients
inM
Cough
1 (17)
1 (33)
0
5 (24)
7 (19)
Hypotension
0
0
4 (67)
3 (14)
7 (19)
- 11/18 (61%) patients who were lenalidomide-naive
· Pathologically-confirmed diagnosis of MM
change
Insomnia
0
1 (33)
2 (33)
4 (19)
7 (19)
- 5/18 (28%) patients who were lenalidomide-pretreated
%
· Measurable disease defined as one of the following:
Muscle spasms
1 (17)
2 (67)
0
4 (19)
7 (19)
· Median duration of objective response:
Best
M-protein 0.5 g/dL in serum
Anemia
1 (17)
0
1 (17)
4 (19)
6 (17)
217 days (range, 28-255)
Individual patients
M-protein >0.5 g/24 hours in urine
Back pain
2 (33)
0
0
4 (19)
6 (17)
·
Note: M-protein assessed in serum unless otherwise specified.
Median progression-free survival:
Free light chain (FLC) >10 mg/dL in serum, provided the
Pyrexia
2 (33)
1 (33)
1 (17)
2 (10)
6 (17)
* change in M-protein assessed by UPEP
+ change in involved FLC
serum FLC ratio is abnormal
129 days (range, 14
Vomiting
2 (33)
0
2 (33)
2 (10)
6 (17)
-276)
· 1 prior systemic therapy (other than single-agent
Other Subgroup Analyses
corticosteroids)
Drug-Related Grade 3/4 Adverse Events
Cohort
· ECOG performance status 2
· All 4 patients whose prior best response to lenalidomide was
1
2
3
Expansion
PD had M-protein reduction in this study (range -100 to -14%)
·
Dacetuzumab dose level
4 mg/kg
8 mg/kg
12 mg/kg
12 mg/kg
Total
Adequate baseline lab values including:
Neutropenia
Response
(N=6)
(N=3)
(N=6)
(N=21)
(N=36)
Thrombocytopenia
· All thalidomide-pretreated patients had a reduction in M-protein
Serum creatinine 1.5 times ULN
Complete Response
1
1
2 (6%)
Fatigue
Partial Response
1
1
2
10
14 (39%)
· No relationship was observed between M-protein reduction and
Pancytopenia
Patient Characteristics (N=36)
Minimal Response
1
2
3 (8%)
CD40 expression
Anemia
No Change
3
1
2
4
10 (28%)
ALT increased
· No relationship was observed between M-protein reduction and
Rela
el te
t d to dacetuz
c
u
etuz mab
Progressive Disease
3
3 (8%)
Median age
64.5 (48-83)
Fc
Diarrhea
receptor IIa-H131R and Fc receptor IIIa-V158F
Rela
el te
t d to other study drug
r
Unknown
2
1
1
4 (11%)
Median years since initial diagnosis
3.6 (1-11)
Fluid overload
polymorphisms
Study Design
ECOG performance status
Headache
Note: Best response to date as assessed by the Investigator and classified according to a modified
European Group for Blood and Marrow Transplant criteria. For patients with disease evaluable by FLC
0
14 (39%)
Herpes zoster
only, responses were classified according to the International Uniform Response Criteria for MM.
Objectives
1
18 (50%)
Hyperglycemia
Conclusions
2
4 (11%)
·
Hypotension
Safety profile of the combination of dacetuzumab, lenalidomide,
Median prior cancer-related systemic therapies
Best Percentage Change in M Protein from
4 (2-14)
Best Percentage Change in M-Protein fro
Hypoxia
and weekly dexamethasone
Received prior lenalidomide
18 (50%)
· The combination of dacetuzumab, lenalidomide, and weekly
Insomnia
Baseline by Cohort
Received prior thalidomide
23 (64%)
dexamethasone was well tolerated in patients with MM
· Maximum tolerated dose (MTD) of dacetuzumab when given in
Leukopenia
Myeloma subtype
this combination regimen
Neuropathy peripheral
· MTD was not established; 12 mg/kg dacetuzumab selected as
IgG
21 (58%)
eline
Osteonecrosis
recommended dose in this combination
IgA
6 (17%)
· Additional objectives:
bas
Light chain
9 (25%)
Renal failure acute
om
· The 61% ORR of dacetuzumab, lenalidomide, and weekly
Clinical response (per modified European Bone Marrow and
Sepsis
fr
Measurable disease assessed by
dexamethasone in lenalidomide-naive patients is comparable to
Transplant criteria)
LC
Serum protein electrophoresis (SPEP)
29 (81%)
Tumor lysis syndrome
F
that of lenalidomide plus standard dexamethasone
Urine protein electrophoresis (UPEP) only
3 (8%)
Progression-free survival
0
5
10
15
20
25
30
35
nor
FLC only
4 (11%)
% patients with a Grade 3 or 4 AE related to study drug
· The 28% ORR in patients previously treated with lenalidomide
oteipr
is encouraging
Study Treatment
Dose-Limiting Toxicities
· A randomized study would be required to determine the
Patient Disposition (N=36)
·
einM-
Diphenhydramine and acetominaphen were given prior to
contribution of dacetuzumab to this combination regimen
dacetuzumab, and 10 mg dexamthosone was added on
· Two DLTs were observed in the study; both resolved:
hang
Median number of cycles received
5 (1-8)
c
Day 4 of Cycle 1
Cohort 1: Grade 3 herpes zoster in a patient post-ASCT
t%
Number of patients still receiving treatment
4
Bes
DISCLOSURES: E Agura, R Niesvizky, J Matous, N Munshi, M Hussein, RV Parameswaren,
· Maximum cycles permitted was 8 in the absence of disease
Completed treatment per protocol
11 (31%)
Cohort 3: Grade 4 renal failure in a patient with IgA
S Tarantolo, and J Zonder received research funding from Seattle Genetics, Inc. to conduct this trial.
progression, or 2 cycles beyond a complete response
Individual patients
R Niesvizky received research funding from and is on the speakers' bureau for Celgene Corporation and
myeloma, rising M-protein, and deteriorating kidney
Reason for early treatment discontinuation
Millennium Pharmaceuticals, and received research funding from Proteolix, Inc. J Matous is on the
· An expansion cohort was treated at the highest dacetuzumab
function at study entry; renal function improved and patient
Note: M-protein assessed in serum unless otherwise specified.
speakers' bureau and received honoraria from Celgene Corporation. N Munshi has membership on
Disease progression or relapse
12 (33%)
* change in M-protein assessed by UPEP
Celgene Corporation's board of directors or advisory committees. J Zonder received research funding from
dose level; half of the patients were lenalidomide-naive
became dialysis-independent
Adverse event
8 (22%)
+ change in involved FLC
Millennium Pharmaceuticals, is a consultant for Amgen, Inc. and Pfizer, Inc., and is on the speakers'
bureau for Celgene Corporation. N Whiting and J Drachman are employed by and have equity ownership
Patient withdrew consent
1 (3%)
in Seattle Genetics, Inc.
Abstract No. 2870
51st ASH Annual Meeting, December 58, 2009