PX-171-006: Phase Ib multicenter dose escalation study of
carfilzomib (CFZ) plus lenalidomide (LEN) and low dose
dexamethasone (loDex) in relapsed and refractory multiple
myeloma (MM) -- Preliminary results
R Niesvizky (1), M Wang (2), B Bensinger (3), M Alsina (4),
M Vallone (5), AA Gutierrez (5), and M Kauffman (5)
(1) Weill Cornell Medical College, New York, NY 10021
(2) M.D. Anderson Cancer Center, Houston, TX 77030
(3) Fred Hutchinson Cancer Research Center, Seattle, WA 98103
(4) H. Lee Moffitt Cancer and Research Center, Tampa, FL 33612
(5) Proteolix, Inc., South San Francisco, CA 94080
Carfilzomib:
Selective and Irreversible Proteasome Inhibitor
Preclinical Characteristics
Good tolerability (no neurotoxicity)
Novel Structure
Sustained target inhibition
High target selectivity
Improved antitumor activity
Irreversible mechanism
Overcomes bortezomib resistance
Tetrapeptide
O
O
H
H
O
N
N
N
N
N
H
H
O
O
O
O
Ketoepoxide
Carfilzomib (CFZ)
Demo SD Cancer Res. 2007; Kuhn DJ Blood. 2007; Kirk, CJ ASH 2008 (Abstract 2765); Arastu-Kapur ASH 2008 (Abstract 2657)
PX-171-006: Rationale for combining Carfilzomib
with Len/Dex in Relapsed / Refractory MM
Carfilzomib is active as single-agent in relapsed MM
Bortezomib naïve: ORR 57%, TTP 11.1 months
Bortezomib pre treated: ORR 18%, TTP 8.3 months
Lenalidomide+Dexamethasone is a current standard of care for
relapsed MM
The combination of Bortezomib with Len/Dex (RVD) is very active in
relapsed / refractory patients but has toxicity limitations (Richardson,
ASH 2008 #1742)
Bortezomib 1 mg/m2 and Lenalidomide 15 mg
The ORR (CR/nCR+ VGPR + PR + MR) was 86% (N=63)
Prior therapies: Len, 8%; Btz, 55%; Thal 77% and SCT 36%
Discontinuations in 19/63 (30%) prior to completing 8 cycles
C+Ld (CRd) should provide superior activity to Ld alone and can allow
long term dosing with full (CRd) regimen given lack of overlapping
toxicities and no significant neuropathy
PX-171-006 /Phase 1b - Carfilzomib + Len/Dex
in Relapsed / Refractory MM
Primary Objective
To evaluate safety and the determine the maximum tolerated dose
(MTD) of carfilzomib with lenalidomide and low dose dexamethasone in
relapsed multiple myeloma subjects
Secondary Objectives
To observe early evidence of efficacy and to collect blood for
pharmacokinetic parameters of carfilzomib
PX-171-006: Carfilzomib + Len/Dex in Relapsed /
Refractory MM
Study Design
Phase 1b, multi-center, escalation trial
Relapsed MM: 13 prior treatments
Study Treatment
(28 day cycles)
Cycles 1-8:
CFZ Days 1, 2, 8, 9, 15, 16
Len Days 1-21
Dex Days 1, 8,15, 22
Cycles 9-16:
CFZ Days 1, 2, 15, 16
Len Days 1-21
Dex Days 1, 8,15, 22
PX-171-006: Dose Cohorts
Primary Dose Cohorts
Carfilzomib
Lenalidomide
Cohort
(mg/m2)
(mg)
1
15
10
2
15
15
3
15
20
4
20
20
5
20
25
6
20/27*
25
* 20mg/m2 on Cycle 1, Days 1 and 2; 27 mg/m2 thereafter
PX-171-006: Eligibility
Relapsed or progressive disease after 1- 3 prior therapies
M protein > 1 g/dL SPEP or monoclonal light chain > 200 mg by 24-hour
UPEP within the past 4 weeks
If previously treated with lenalidomide or bortezomib, the subject
must not have progressed during the first 6 months of treatment
ECOG 0-2 PS
Neuropathy permitted at baseline (G 1/2 without pain)
Hemoglobin > 8 g/dL
Platelet count > 50,000/mm3
Absolute neutrophil count > 1,000/mm3
Bilirubin < 2 mg/dL, ALT and AST < 3 times ULN
Creatinine < 2 mg/dL or CrCl > 50 mL/min
PX-171-006: Evaluation
Response
Overall response (CR, sCR, VGPR, PR) - IWG criteria
Secondary assessment by modified EBMT criteria for MR
Adverse Events
Common Terminology Criteria for Adverse Events (CTCAE) version 3.0
Dose limiting toxicity (DLT) defined as:
Grade (G) 3 non-hematologic
G4 neutropenia for > 7 d and / or neutropenic fever
G4 thrombocytopenia > 7 d
G3-G4 thrombocytopenia in association with bleeding
MTD = Dose level prior to that resulting in 2/6 DLTs
IMWG, International Myeloma Working Group; EBMT, European Group for Blood and Marrow Transplantion;
CTC, NCI Common Toxicity Criteria
PX-171-006: Baseline Characteristics (N = 20)
Characteristic
Median (range)
Age, years
60.5 (43-81)
Time since diagnosis, years
2.8 (1.48-14.53)
N (%)
Male
12 (60)
Gender
Female
8 (40)
Immunoglobulin
IgG
16 (80)
subclass
IgA
4 (20)
Baseline evaluation
History of neuropathy
14 (70)
PX-171-006: Prior Therapies (N = 20)
Prior Therapies
Median (range)
Number
2.5 (1-3)
%
Bortezomib
80
Immunomodulatory agents
90
Lenalidomide
65
Thalidomide
40
Corticosteroid
95
Alkylating agents
80
Anthracycline
35
Stem cell transplant
90
Refractory to at least 1 prior therapy
30
PX-171-006: Disposition (N= 24)
Number
CFZ (mg/m2) /
Number of 28 Day
Cohort
DLTs
of Patents
LEN (mg)
Cycles
1
6
15 / 10
10, 10, 4*, 3*, 2*, 1*
0
2
6
15 / 15
7, 7, 6, 5, 1*, 1*
0
3
8
15 / 20
4, 4, 3, 3, 3, 3, 3, 0*
0
4
4
20 / 20
2, 1, 1, 1
0
* Off study
PX-171-006: Treatment Emergent Toxicities (N=20)
n (%)
Adverse Events 20%
All Grades
Grade 3/4
Anemia
7 (35)
4 (20)
Fatigue
7 (35)
Diarrhea
5 (25)
Muscle spasms
5 (25)
Neutropenia
5 (25)
2 (10)
Insomnia
4 (20)
Nausea
4 (20)
Thrombocytopenia
4 (20)
4 (20)*
Drug-related SAEs
0
Drug-related DLTs
0
AEs resulting in discontinuation
1 (5)
Deaths
0
* Single G4 thrombocytopenia less than 7 days (no DLT)
PX-171-006: Toxicity
Discontinuation
Cohort 3: CRD d/c on C1D2 due to G2 Fever
Dose Reduction
Cohort 2: Len on C1D8 due to G2 fatigue and G2 anorexia
No peripheral neuropathy adverse events reported
No significant fatigue ( G3) or thrombotic events
No DLTs were reported through cohort 3
PX-171-006: Activity in Evaluable Patients (N=18)
CFZ (mg/m2) /
Cohort
N
VGPR
PR
MR
SD
PD
LEN (mg)
1
15 / 10
6
3
0
1
2
2
15 / 15
5
1
2
1
0
1
3
15 / 20
7
2
1
1
3
61% Objective response (CR + VGPR + PR + MR)
Responses were rapid and occurred within the first 28-day cycle
Responses are improving with continuing therapy ( 3 months)
PX-171-006: Responses to Sub-MTD Doses of
Carfilzomib + Len / Dex are Durable (N=15)
Maximum Confirmed
Treatment Duration
M Protein Change (%)
(Days)
*
29
VGPR
76
6
26
PR
5
3
**
56
27
28
51
MR
54
11
SD
9
1
10
**
-100
-50
0 0
100
200
300
* nCR: IFE positive
**Off study
Lenalidomide - Dexamethasone Does Not Alter
Carfilzomib Mediated Proteasome Inhibition
Proteasome Activity (Chymotrypsin-like Site)
CFZ 15 mg/m2
RBC
PBMC
120
e)
120
100
100
redos 80
80
vity P
ti 1 60
60
c D1C 40
A
40
of 20
20
(%
0
0
pre
1hr
Pre
1hr
pre
1hr
Pre
1hr
Cycle 1
Cycle 2
Cycle 1
Cycle 2
Potent (70 80%) inhibition of chymotrypsin-like sites (Beta5 & LMP7)
Recovery of Proteasome Activity in PBMC between cycles
Equivalent proteasome inhibition in PBMC in Cycle 2
PX-171-006: Conclusions
Carfilzomib + Len/Dex is well tolerated in heavily pre treated subjects
Majority of patients had received bortezomib and IMiDs
MTD not yet reached - No DLTs
Manageable expected hematological events
Peripheral neuropathy has not been observed
Prolonged administration possible (> 9 months)
Carfilzomib + Len/Dex yielded responses in the majority of subjects
61% objective response (CR+VGPR+ PR+MR)
Doses well below the single agent MTD of either LEN or CFZ
Responses improve with continuing therapy (3 months)
Dose escalation ongoing
Next cohort: 20 mg/m2 CFZ/ 25 mg/day lenalidomide
Phase 3 trial to be initiated in 2010
Lenalidomide/dexamethasone +/- carfilzomib
Acknowledgements
MD Anderson Cancer Center
Dr Michael Wang's team
Weill Cornell Medical College, New York, NY
Dr Ruben Niesvizky's team
Fred Hutchinson Cancer Research Center
Dr William Bensinger's team
H. Lee Moffitt Cancer and Research Center
Dr Melissa Alsina's team
Proteolix, South San Francisco
The Patients and their Families