Phase II Trial of weekly bortezomib in
combination with CCI-779 (temsirolimus)
() in
Relapsed or Relapsed/Refractory Multiple
Myeloma
Irene M.Ghobrial1*, Ravi Vij2; Nikhil C. Munshi1; Robert
Schlossman1; Jacob Laubach1; Andrzej Jakubiak3; Renee Leduc1,
Meghan Rourke1
Rourke , Stacey Chuma1
Chuma , Janet Kunsman1
Kunsman , Akari M
Dollard1,4; Diane Warren1, Brianna Harris1, Amy Sam1, Kenneth C.
Anderson1, and Paul G. Richardson1
1Dana-Farber Cancer Inst., Boston, MA; 2University of Washington, St
Louis, MO; 3University of Michigan, Ann Arbor, MI, 4Multiple Myeloma
Research Consortium (MMRC), Norwalk, CT.
Introduction
· This study aimed to determine activity and safety of
weekly bortezomib (Millennium/Takeda Inc, MA) and
CCI 779
-
(temsirolimus, Wyeth, PA) in patients with
relapsed/refractory MM.
· The phosp
pphatidylinositol-3, kinase (PI3K)
() pathwa
p
y is
important in enhancing cell survival by stimulating cell
proliferation and inhibiting apoptosis.
· mTOR inhibition (CCI 779)
-
may
may overcome resistance
to bortezomib in vivo.
mTOR inhibition overcomes resistance
to bortezomib
Ra p a m y c i n ( n M )
0
Si
Synergisti
tic
40
5
response even
in the presence
30
of endothelial
)
3
0
20
ll
ce s
(1
Cpm
10
0
0
1
50
150
15
H U V E C
M M . 1S
C o cu l t u r e
Bo r t e z o m i b ( n M )
P AKT
Inhibition
-AKT
of pS6 and
P-S6R
ERK in
P-ERK
response
tubulin
to mTOR
0 B5 R5 B5+R5 0 B5 R5 B5+R5
stromal
Objectives
·Primary Objective:
· Assess response rate (CR+PR+MR) in patients treated
with the
the combination
·Secondary Objectives: update
1- Evaluate toxicity
toxicity specifically
specifically neurotoxicity
2- Correlative studies on tumor cells before/after therapy
3- Examine the effect on osteoclast activity (NTX level)
4- Determine progression-free survival and overall
survival
Phase I dosing schedule
Dose lev
el
N=20
Assigne
dtherap
y. Acycl
e= 35 days
Level 1
3
Bortezomib1.3mg/m2 day 1
, 8, 15 and22.
CCI77
CCI
- 9
77 15
1 mg
m days
day 1, 8, 15
1 , 22
2 , and
an 29
2 .
Level 2
3
Bortezomib1.6mg/m2day1, 8,15 an
d 22.
CCI
-77
CCI 9
77 15
1 mg
m days
day 1, 8, 15
1 , 22
2 , and
an 29
2 .
Level 3
5
Bortezomib1.3mg/m2 day 1
, 8, 15 and22.
CCI
-77925mgdays1, 8, 15, 22, and29.
Level
4*
9
Bortezomib1.6mg/m2 day 1
, 8, 15 and22.
*Curren
t phas
eII dose
CCI
-77925mgdays1, 8, 15, 22, and29.
Inclusion/Exclusion criteria
1)
Patients with relapsed or relapsed/refractor
pp
y MM
with any prior lines of therapy including bortezomib
2)
Measurable disease
3)
No chemotherapy within 3 weeks, or
biological/novel therapy for MM within 2 weeks.
4)
No prior mTOR
mTOR inhibitors
inhibitors
5)
Exclusion: high cholesterol and triglycerides.
6)
Dexamethasone was not permitted during
pg
therapy.
Results
· 38 patients have been enrolled to date
· Of these, 31
31 are
are evaluable as they
received at least 1 cycle of therapy.
· The other
other patients:
­ Did not complete the first cycle as of the
date of
of analysis (N=4)
(N=4)
­ Withdrew consent within the first cycle
(N=3)
Baseline characteristics= 38
Gender
Male: 18
18
46%
Female: 21
54%
Age at enrollment
Median: 63
Range, 40-78
Durie Salmon at diagnosis
1
5
13
2A
11
28
2B
1
3
3A
16
41
3B
1
3
Unknown
5
13
ISS at diagnosis
I
17
44
II
10
26
III
7
18
Unknown
5
13
Lines of therapy
Median = 4
Range, 1-8
One: 3
8%
Two: 8
20%
Three: 5
13%
Four and more:23
59%
Prior bortezomib
N 29
74%
Disease status
Relapsed: 19
49%
Refractory:20
51%
Response N=31
The ORR (including
ding MR)
MR) was 19/31 (61%)
CR and nCR
3 (10%)
VGPR
2(6%)
PR
6(20%)
MR
8 (27%)
St bl
a e disease
9 (27
(
%
27 )
Progressive
g
disease
3(10%
(
)
Toxicity
N=38
Grade 3/4
Lymphopenia
7 (18%)
Thrombocytopenia
6 (16%)
Neutropenia
5 (13%)
Anemia
3(
3 8%)
(8%)
GI toxicity (diarrhea, nausea and anorexia)
3 (8%)
Infections (pneumonia
(p
, sepsis
p
and others
5 (13%)
()
including H1N1
Pulmonary Hge and GI bleed
2 (1 of each) (5%)
Hyperglycemia
2(
2 5%)
(5%)
Neuropathy
0
Death
2 (5%), cardiac and sepsis with
plasma cell leukemia progression
·Dose reductions occurred in 8 (21%) due to diarrhea, neutropenia, and
pulmonary toxicity.
Conclusion
· Thecombination of weekly bt
bortezomib
ib and
CCI-779 showed an exciting response rate in
patients with relapsed or refractory multiple
myeloma, with at least MR or better seen in
63% of patients to date.
· Cytopenias were the most common toxicities,
specifically thrombocytopenia, as well as GI
toxicity,
but
overall
side
effects
proved
manageable.
Acknowledgment
·DFCI:
·DFCI physicians/NP: Paul Richardson, Ken Anderson, Nikhil
Munshi, Robert Schlossman, Jacob Laubach, Phillip Armand, Janet
Kunsman, Mary Mckenney, Kim Noonan.
·DFCI Clinical Research Team: Stacey Chuma, Renee Leduc,
Meghan Rourke, Diane Wa
W rren
a
, Amy
Amy Sam, Tif
Ti fany
ffany Poon, Brianna
Harris
·Statistical Team: Edie Weller
·MMRC: Akari Dollard
·University of Washington:
W
Ravi Vi
Vij
·University of Michigan: Andrzej Jakubiak
·Our patients and families
S
· upported in part by MMRC, LLS, Mill
i
enn um/T
/Takeda
d
an Wyeth
th Inc.