Phase I Study of the Safety and Efficacy of
Bortezomib (VELCADE®) in Combination With
Lenalidomide (REVLIMID®) in Relapsed and
Refractory Multiple Myeloma: Preliminary Results
P.G. Richardson,1 R. Schlossman,1 N. Munshi,1 D. Avigan,1 S. Jagannath,2
M. Alsina,3 D. Doss,1 Kathleen Colson,1 M. McKenney,1 K. Hande,1 S. Gorelik,1
C. McAlister,1 A. Freeman,1 Diane Warren,1 C. Mitsiades,1 T. Hideshima,1
R. R. Michelle,1 K. Balinski,5 C. Byrne,5 C. Chrystal,5 T. Myers,4 E.Trehu,4
R. Knight,5 D. Schenkein,4 K.C. Anderson1
1Dana-Farber Cancer Institute, Boston, MA;
2St. Vincent's Cancer Center, New York, NY;
3Moffitt Cancer Center, Tampa, FL;
4Millennium Pharmaceuticals, Inc., Cambridge, MA;
5Celgene, Inc., Warren, NJ
Bortezomib
·
Potent anti-MM activity preclinically (via caspases -8,-9,-3)1
·
Phase 1: MTD of 1.3 mg/m2 twice wkly for 2 wks followed by 1 wk rest2
·
Efficacious and safe in phase 2 trials: SUMMIT3, CREST4
·
Pivotal phase 3 randomized trial (APEX5, n = 669):
significant improvement in TTP, survival in pts with 13 prior therapies
·
Under study in 7 front-line combination trials with RR 7395% CR/near
CR 1729% [ASH 2004]
1. Hideshima et al. Cancer Res. 2001;61:3071.
2. Orlowski et al. J Clin Oncol. 2002;20:4420-4427.
3. Richardson et al. N Engl J Med. 2003;348:2609.
4. Jagannath et al. Br J Haematol. 2004;127:165-172.
5. Richardson et al. J Clin Oncol. 2004;22:560s.
Lenalidomide
·
Potent preclinical activity in MM in vitro, in vivo 1-4
·
Active and safe in MM: responses with 50% M-protein reduction:
· 2440% of pts receiving lenalidomide +/- dex, with relapsed and
relapsed, refractory MM, including pts who received prior
bortezomib 5-7
· 25 of 30 patients (83%) with newly diagnosed MM receiving
lenalidomide and dex 8
·
Recent interim results of 2 large phase 3 trials showed superiority of
lenalidomide with dex compared with dex in pts with relapsed MM 9
1. Hideshima T et al. Blood. 2000;96:2943.
5. Richardson PG et al. Blood. 2002;100:3063
2. Davies FE et al. Blood. 2001;98: 210.
6. Zangari et al. Blood. 2003;102:450a.
3. Mitsiades C et al. Blood. 2002; 99: 4525.
7. Richardson et al. Blood. 2003;102:235a.
4. Lentzsch S et al. Cancer Res. 2002; 62: 2300.
8. Rajkumar et al. Blood. 2004;104:98a.
9. Weber et al. IMMW 2005
Combination of bortezomib + lenalidomide
50
Patient cells
40
Lenalidomide
100
0 uM
5 uM
80
30
eath
60
d
control
20
% 40
cell%
20
10
0
0
10
20
Bortezomib (nM)
0
ib
ide
ide
ib
m
ide
tezom
ezo
m
tezom
ez
nalido
nal
bor
nalido
nal
Mitsiades et al, Blood 2003
Le
bor
Le
+
Rationale
· Lenalidomide potentiates the apoptotic effects of bortezomib
in preclinical studies1
· Expected overlapping toxicities manageable (primarily
hematologic) 2
· In phase 1:
· MTD of lenalidomide 25 mg (PO daily,28-day cycle)2, 3
· MTD of bortezomib 1.3 mg/m2 (IV twice wkly,21-day cycle)4
1. Mitsiades et al. Blood. 2003
2. Richardson et al. Blood. 2002
3. Zangari et al. Blood. 2003
4. Orlowski et al. J Clin Oncol. 2003
Objectives
· Primary
· Evaluate safety of combination in pts with
relapsed or relapsed/refractory MM
· Identify MTD and recommended dose for phase 2
· Secondary
· Evaluate response
· Assess PK
· Explore PGX/ surrogate markers
Schema
Lenalidomide, mg
Bortezomib, mg/m2
5
10
15
20
1.0
Cohort 1
Cohort 3
Cohort 5
Cohort 7
1.3
Cohort 2
Cohort 4
Cohort 6
Cohort 8
· 8 cohorts of 36 pts, with additional 10 pts enrolled at the MTD
21-day cycle*
1
4
8
11
14
21
B
B
B
B
Lenalidomide daily
*For a maximum of 8 cycles; for pts with PD Dex added
(20mg day of and day following bortezomib): extension phase for pts in response
Eligibility
· Inclusion criteria:
· Relapsed or relapsed, refractory MM (at least 1 prior
therapy)
· Age > 18 years
· ECOG performance status 02
· Prior thalidomide, lenalidomide and bortezomib
permitted
· Women of childbearing potential: negative pregnancy
test
Eligibility
· Exclusion criteria:
· Creatinine > 2 mg/dL
· Concomitant corticosteroids, chemotherapy, or
radiation
· PNY grade 3 or grade 2 with pain
· Platelets < 50,000 cells/mm3
· ANC < 1,000 cells/mm3
· Hgb < 8.0 g/dL
· AST 2 × ULN
· Intolerance to bortezomib or lenalidomide or
hypersensitivity to thalidomide
· Pregnancy
Evaluation
· Response using EBMT criteria1 (after 2 cycles and after
every subsequent cycle)
· Adverse events assessed using NCI CTC version 3.0
· Dose-limiting toxicity (DLT)
· Nonhematologic toxicity grade 3
· Thrombocytopenia with platelets < 10,000/mm3 on
more than 1 occasion despite transfusion support
· Neutropenia occurring for more than 5 days and/or
resulting in neutropenic fever
· MTD: dose level prior to that resulting in 2 DLTs
1. Bladé et al. Br J Haematol. 1998;102:1115.
Results
Baseline Characteristics (N = 12)
Characteristic
Median age, y (range)
59 (3775)
Male, %
42
Myeloma type, %
IgG
83
IgA
17
Durie-Salmon stage III, %
25
Disease status
Relapsed, n
6
Relapsed and refractory, n
6
Median no. of prior therapies (range)
4 (1-9)
Prior SCT
8 (66%)
Prior bortezomib
4 (33%)
Prior lenalidomide
2 (17%)
Prior thalidomide
9 (63%)
Disposition
N
Enrollment
12
Evaluable for response*
11
Cohort 1
3
Cohort 2
3
Cohort 3
3
Cohort 4
2
Cohort 58
0
*Confirmed at cycle 2 and at each subsequent cycle.
Adverse Events
Cohort
Cycle
Adverse Event
Grade 4 neutropenia*
1
3
(ANC 420/µL in 1 pt)
Grade 3 thrombocytopenia
2
2, 4
(32,000 in 2 pts)
Grade 4 neutropenia*
3
1
(ANC 300/µL in 1 pt)
Grade 3 hyponatremia
4
1
(Na 129 mmol/L in 1 pt)
*Less than 5 days (not DLT)
Determined to be drug related (DLT)
Toxicity
·
No discontinuations
·
No significant PNY, fatigue
·
No DLT through first 3 cohorts
·
One DLT in cohort 4
Grade 3 hyponatremia
·
4 additional pts will be enrolled in cohort 4
@ Bortezomib 1.3 mg/m2, lenalidomide 10 mg
·
Dose reductions of bortezomib (1.3 to 1.0 mg/m2) (n=4),
lenalidomide (10 to 5 mg) (n=1) beyond cycle 2 (neutropenia,
thrombocytopenia)
·
MTD not yet reached
Response (n= 11*)
No. of
Cohort
Regimen
Response
Cycles
Bortezomib 1.0 mg/m2
PR: 1 of 3
1
810
+ lenalidomide 5 mg
MR: 2 of 3
Bortezomib 1.3 mg/m2
CR: 1 of 3
2
78
+ lenalidomide 5 mg
PR: 2 of 3
Bortezomib 1.0 mg/m2
56
PR: 2 of 3
3
+ lenalidomide 10 mg
2
PR: 1 of 3
Bortezomib 1.3 mg/m2
PR: 1 of 2
4
2
+ lenalidomide 10 mg
PD**: 1 of 2
*Evaluable **Dex added
RR (CR + PR + MR) : 91%
Summary
· Encouraging safety profile and activity of
bortezomib plus lenalidomide in heavily
pretreated pts
· Further investigation ongoing to determine MTD
· Enrollment of additional 10 pts at MTD
· Complete PK, surrogate marker analysis
Future Directions
· Phase 2 studies in relapsed and
relapsed refractory MM
· Phase 2 study in newly diagnosed pts
Acknowledgements
· Dana-Farber Cancer
·Millennium
Institute:
Pharmaceuticals Inc
· CRC nursing team
· Research pharmacy
·Celgene Inc
· St. Vincent's Comprehensive
·Moffitt Cancer Center
Cancer Center:
Clinical Research
Coordination Team
· MMRF and IMF
The Patients and Their Families