Tanespimycin + Bortezomib in
Patients With Relapsed and
Refractory Multiple Myeloma:
Final Results of a Phase 1/2 Study
PG Richardson,1 A Chanan-Khan,2 S Lonial,3 A Krishnan,4 M Carroll,5
M Alsina,6 M Albitar,7 D Berman,8 S Kaplita,8 KC Anderson1
1Dana-Farber Cancer Institute, Boston, MA, USA; 2Roswell Park Cancer Institute, Buffalo, NY, USA;
3Emory University, Winship Cancer Institute, Atlanta, GA, USA; 4City of Hope, Duarte, CA, USA;
5Sutter Regional Cancer Institute, Sacramento, CA, USA; 6H. Lee Moffitt Cancer Center, Tampa, FL, USA;
7Quest Hematopathology, San Juan Capistrano, CA, USA; 8Bristol-Myers Squibb, Princeton, NJ, USA
Tanespimycin + Bortezomib in Myeloma, Phase 1/2
Disclosures
Advisory Board
Bristol-Myers Squibb Company
Millennium Pharmaceuticals, Inc.
Celgene Corporation
Speakers Bureau
Millennium Pharmaceuticals, Inc.
Celgene Corporation
Tanespimycin + Bortezomib in Myeloma, Phase 1/2
Tanespimycin Rationale for
Combination With Bortezomib
· Tanespimycin disrupts Hsp90, a key molecular
chaperone for signal transduction proteins, critical to
myeloma (MM) growth, survival, drug resistance.1
· MM cells are more dependent than normal cells on
Hsp90 for survival.
· Tanespimycin has preclinical activity in MM cells
resistant to other therapies, incl. bortezomib.1
· Tanespimycin as monotherapy is well tolerated with
modest activity in relapsed/refractory MM.2,3
· Preclinical data show antitumor synergy with
bortezomib, as well as other therapies.1
1. Mitsiades CS et al., Blood, 2006.
2. Mitsiades CS et al., ASCO 2005; Abstract 3056.
3. Richardson PG et al., ASH 2005; Abstract 361.
Tanespimycin + Bortezomib in Myeloma, Phase 1/2
Tanespimycin + Bortezomib:
Preclinical Rationale in MM
Synergistic Antitumor Activity*
Enhanced Proteasome Inhibition*
120
120
100
100
rol)
80
rol)
80
Survival
Activity
cont
60
cont
60
Cell
of
of
(%
40
(%
40
Tumor
20
Proteasome
20
0
0
ib
+
ib
+
n
trol
ycin
ib
trol
ycin
ib
m
yci
ycin
Con
spi
tezom
pim
Con
Bortezom
ne
Bor
Ta
Bortezom
Tanespim
Bortezom
Tanes
Tanespim
*These assays were performed on bortezomib-resistant MM cells.
Mitsiades CS et al., Blood, 2006.
Tanespimycin + Bortezomib in Myeloma, Phase 1/2
Tanespimycin + Bortezomib Phase 1/2 Trial in
Relapsed/Refractory MM ­ Study Design
+
+
+
+
ycin
ycin
ycin
ycin
m
m
m
m
Cycle
Assess
Tanespi
Bortezomib
Tanespi
Bortezomib
Tanespi
Bortezomib
Tanespi
Bortezomib
Day
1
4
8
11
21
·
Phase 1 dose escalation (n=30)1
­
Tanespimycin 100 to 275 mg/m2
­
Bortezomib 0.7 to 1.3 mg/m2
­ 14 pts received 0.7 to 1.0 mg/m2
­ 16 pts received 1.3 mg/m2
·
Phase 2 expansion at highest tested dose: tanespimycin 340 mg/m2 and
bortezomib 1 to 1.3 mg/m2 (n=42)
·
MM response reported every 6 wks (modified EBMT criteria2,3)
·
Pts treated for up to 8 cycles and then until progression (PD)
1. Richardson PG et al., ASH 2006; Abstract 406 (Oral).
2. Bladé J et al., Br J Haematol, 1998.
3. Richardson PG et al., N Eng J Med, 2003.
Tanespimycin + Bortezomib in Myeloma, Phase 1/2
Key Eligibility Criteria
· Pts with relapsed/refractory MM following 2 or more prior
therapies
­ Prior bortezomib and Hsp90 inhibitors permitted
­ Prior therapy could include SCT
· At least 3 wks since last dose of prior therapy;
4 wks since SCT
· Pts with no measurable disease were allowed.
· KPS >70; adequate organ function
· Adverse events from prior therapy resolved to G2
Tanespimycin + Bortezomib in Myeloma, Phase 1/2
Baseline Characteristics
N=72
Median age, yrs
60
% Subtype, IgG / IgA / Non-secretory
72/27/6
2 microglobulin, median in mg/dL
3.6
Mos since diagnosis, median
50.5
Number of prior regimens, median (range)
5 (1­15)
SCT
69%
Thalidomide
74%
Lenalidomide
28%
Bortezomib-naive
31%
Bortezomib-pretreated
33%
Bortezomib-refractory
36%
Hsp90 inhibitors
10%
Tanespimycin + Bortezomib in Myeloma, Phase 1/2
Best Response
CR + PR + MR,
n (%)
Total, N=67*
18 (27)
Bortezomib Status at Study Entry
Naive, n=21
10 (48)
3 prior regimens, n=11
7 (64)
4 prior regimens, n=10
3 (30)**
Pretreated, n=23
5 (22)
Refractory, n=23
3 (13)
CR, complete response; MR, minimal response; PR, partial response.
*Evaluable pt cohort excludes 2 pts with no M protein at baseline
and 3 pts who received lowest doses of tanespimycin + bortezomib
**Includes 1 pt who received a SCT prior to 6-wk confirmation of response
Tanespimycin + Bortezomib in Myeloma, Phase 1/2
Duration of Response of Pts Responding to
Tanespimycin + Bortezomib
Duration of Response, mos
Bortezomib-naive, n=10
3, 5, 5, 7, 11, 11, 11, 19, 27, 27
Bortezomib-pretreated, n=5
2, 2, 12, 18, n/a
Bortezomib-refractory, n=3
10, 19, 21
Median duration of response (all responders): 12 mos (95% CI: 5­19)
Tanespimycin + Bortezomib in Myeloma, Phase 1/2
Durable PRs in Bortezomib-refractory Pts
Pt 501 (62 yr man)
· Prior to Study Entry: PD on bortezomib/dex, PD on thal/dex
· On Study: confirmed PR through 21.5 mos
Pt 704 (58 yr woman)
· Prior to Study Entry: 7 regimens. Last Rx: bortezomib/thal/dex with
PD
· On Study: confirmed PR through 12.1 mos
Pt 605 (58 yr woman)
· Prior to Study Entry: 3 regimens. Last Rx: bortezomib/dex with PD
· On Study: confirmed PR through 26.5 mos
Tanespimycin + Bortezomib in Myeloma, Phase 1/2
Progression-free Survival
1.0 +
N=72
Median PFS, mos
+
Bortezomib-naive, n=22
7.2 (95% CI, 4.2­15.0)
0.8
+
Bortezomib-pretreated, n=24 3.7 (95% CI, 1.5­5.1)
Bortezomib-refractory, n=26
1.6 (95% CI, 1.0­2.3)
0.6
Surviving
+
0.4
+ +
+
0.2
Proportion
+
+
+
+
+
0.0
0
10
20
30
Months
PFS was based on EBMT criteria1, all patients.
1. Bladé J et al., Br J Haematol, 1998.
Tanespimycin + Bortezomib in Myeloma, Phase 1/2
Overall Survival
1.0
++
+
+ ++ +
+ ++
+++ +
++
++ +
++++
0.8
+
+
+ + ++
0.6
++
Surviving
+
+
0.4
+
+
+
++
+
N=72
Median OS, mos
+
+
Proportion 0.2
Bortezomib-naive, n=22
NR (95% CI, 36.8­NR)
Bortezomib-pretreated, n=24
17.7 (95% CI, 12.5­37.9)
Bortezomib-refractory, n=26
13.8 (95% CI, 7.8­36.3)
0.0
0
10
20
30
40
Months
NR, not reached.
Median OS for all 72 pts: 18 mos (95% CI, 13­36)
Tanespimycin + Bortezomib in Myeloma, Phase 1/2
Hematologic Adverse Events
Tanespimycin + Bortezomib
N=72
AE
All Grades, %
Grade 3/4, %
Thrombocytopenia
40
25
Anemia
15
7
Neutropenia
43
· In previous phase 1 tanespimycin monotherapy study in relapsed and
refractory MM, no neutropenia observed1
· In APEX (phase 3 study of bortezomib as monotherapy in
relapsed/refractory MM): 14% G3/4 neutropenia2
1. Richardson PG et al., ASH 2005; Abstract 361.
2. Richardson PG et al., N Engl J Med, 2005.
Tanespimycin + Bortezomib in Myeloma, Phase 1/2
Key Non-Hematologic Adverse Events
Tanespimycin + Bortezomib
N=72
AE
All Grades, %
Grade 3/4, %
Diarrhea
60
7
Nausea
49
3
Fatigue
49
7
AST elevation
28
4
Dizziness
28
1
Vomiting
24
1
Constipation
21
0
Peripheral neuropathy (PN)
21
0
Anorexia
60
· LFT abnormalities reversible and manageable with dose modification and/or
ursodiol
· In APEX, all Grades: constipation 42% (2% G3/4); anorexia 23% (3%);
PN 36% (8%)1
1. Richardson PG et al., N Engl J Med, 2005.
Tanespimycin + Bortezomib in Myeloma, Phase 1/2
Tanespimycin Neuroprotection in von Frey Model
of PN in Rats
Tanespimycin + bortezomib, twice wkly
70.0
Bortezomib, twice wkly
)g
Bortezomib, twice wkly;
( 65.0
d
Tanespimycin added on day 29
60.0
55.0
Threshol 50.0
ory
45.0
*
Sens
*
***
40.0
***
***
***
**
35.0
***
***
**
***
Group
**
***
***
30.0
***
**
verage 25.0
A
Rescue with tanespimycin on day 29
20.0
7
9
11
13
15
17
19
21
23
25
27
29
31
33
35
37
39
41
43
45
Dosing
Study Day
*P<0.05, **P<0.01, ***P<0.001 vs Combination
1. Richardson PG et al., ASH 2007; Abstract 1165.
Tanespimycin + Bortezomib in Myeloma, Phase 1/2
Summary
· Tanespimycin + bortezomib induces durable
responses in relapsed/refractory MM, including
bortezomib-refractory pts.
· Tanespimycin neuroprotective in animal models,
reverses bortezomib-induced PN
­ No severe PN observed in this study, c/w preclinical models
· Tanespimycin + bortezomib as long-term therapy is
well tolerated.
­ Low rate of neutropenia
­ Low rates of constipation, anorexia
­ LFT elevation and other AEs manageable and reversible
Tanespimycin + Bortezomib in Myeloma, Phase 1/2
Future Directions
· TIME-1: international phase 3 study of
tanespimycin with bortezomib in relapsed MM
pts (NCT #00546780)
· Phase 3 study of tanespimycin with
bortezomib-based therapy for first-line
treatment of pts with MM planned
· Further studies of the mechanism of action of
tanespimycin neuroprotection underway (role
of Hsp70?)
Tanespimycin + Bortezomib in Myeloma, Phase 1/2
Acknowledgments
· Dana-Farber Cancer Institute
· Roswell Park Cancer Institute
· Emory University, Winship Cancer Institute
· City of Hope
· Sutter Regional Cancer Institute
· H. Lee Moffitt Cancer Center
· Quest Hematopathology
· Research nurses, physicians, coordinators, and other
staff at study sites
· Bristol-Myers Squibb (and previously Kosan
Biosciences)
· The patients and their families