NPI-0052-101
Phase 1 Clinical Trial of the Novel Structure
Proteasome Inhibitor NPI-0052 in Patients with
Relapsed and Relapsed/Refractory Multiple
Myeloma (MM)
Paul Richardson, MD, Craig Hofmeister, MD,
Andrzej Jakubowiak, MD, PhD, Todd M. Zimmerman, MD,
Matthew A. Spear, MD, Sagar Lonial, MD,
Jonathan Kaufman, MD, Asher Chanan-Khan MD,
Michael A. Palladino, PhD, Angie M. Longenecker, RN, BSN,
Susan L. Kelley, MD, Saskia Neuteboom, PhD,
Gillian F Cropp, MSc, G. Kenneth Lloyd, PhD,
Alison L. Hannah, MD and Kenneth C. Anderson, MD
Dana Farber Cancer Institute, Boston, MA
Ohio State University, Columbus, OH
University of Michigan, Ann Arbor, MI
University of Chicago, Chicago, IL
Winship Cancer Center, Atlanta, GA
Roswell Park Cancer Institute, Buffalo, NY
Multiple Myeloma Research Consortium, Norwalk, CT
Nereus Pharmaceuticals, Inc., San Diego, CA
NPI-0052
Novel second generation 20S proteasome inhibitor (non-peptide based)
Unique proteasome inhibition profile:
Fast, marked and prolonged inhibition of all 3 proteolytic activities
Unique toxicology profile:
High levels of proteasome inhibition can be achieved
Toxicities frequently reported with bortezomib do not appear
to be elicited by NPI-0052 at equivalent or greater levels of
proteasome inhibition
Unique activity profile:
Efficacy in tumor models resistant to bortezomib
NPI-0052
H
H OH
H
O
N
O
O
H
CH3
Cl
NPI-0052
Proteasome Inhibition Profile
1 mg/kg Bor tez omib, IV
0.15 mg/kg N PI-0052, IV
10 0
10 0
ity
ity
tiv
e
tiv
e
c
h
75
75
ac
fth
a
ft
e
o
o
n
-lik
*
o
-like
**
tion
in
iti
in
50
50
s
ib
p
ibi
ps
h
h
ry
in
try
in
o
ot
25
25
%
%
m
ym
yh
ch
c
0
0
1.5 hr
2 4 h r
4 8 h r
72 h r
168 h r
1.5 hr
24 hr
4 8 hr
72 h r
1 68 hr
Time
Time
0.15 mg/kg NPI-0052, IV
1 mg/kg B ortez omib, IV
10 0
0
e
eh
75
fth
tivity
t
vity
o
of
cti
n
ac
a
-3 0
o
e
iti
50
tion
*
ib
-liken
*
ibi
-lik
h
h
in
n
n
s
i
i
p
-6 0
25
%
trypsi
%
try
0
-9 0
1 .5 hr
24 h r
48 hr
7 2 hr
1 68 hr
1 .5 hr
24 h r
4 8 hr
72 hr
1 68 hr
Time
Time
0.15 m g/kg N PI-0052, IV
1 mg/kg Bortez omib, IV
10 0
10 0
e
ity
e
ity
iv
h
75
tiv
75
fth
ft
c
o
act
o
a
n
e
e
itio
lik
50
tion
-lik
50
ib
e-
bi
h
s
se
*
n
a
nhi
a
i
p
*
i
sp
25
%
25
%
a
cas
c
0
0
1 .5 hr
24 hr
48 h r
7 2 hr
16 8 hr
1.5 hr
24 h r
4 8 hr
72 hr
168 hr
Time
Time
Chauhan et al., Cancer Cell 2005
NPI-0052 is Active in Bortezomib
Resistant/Refractory Human MM Samples
MM cells from pts refractory
MM cells from pts also
to dexamethasone and thalidomide
refractory to bortezomib
5
Chauhan et al., Cancer Cell 2005
Majority of Mice with Human MM.1S Myeloma
Xenografts Tumor Free After NPI-0052
NPI-0052 administered orally BIW for 13 wks
NPI-0052 well tolerated, prolongs survival with significantly reduced tumor
recurrence
Similar reduced tumor recurrence obtained with NPI-0052 administered IV
6
Chauhan et al., Cancer Cell 2005
NPI-0052 Exhibits a Large
Therapeutic Index Preclinically
IC (nM)
Human
50
IC > 100nM
Cell Type
50
NPI-0052 Bortezomib
RPMI 8226
(multiple
9.1 0.8
5.7 1.3
myeloma)
IC ~ 5-10nM
CCD-27sk
50
(normal
510 160
15 2.7
fibroblasts)
Ratio
56
2.6
CCD:RPMI
The average IC50 value of at least three
experiments. Cells treated for 48h.
7
Chauhan et al., Cancer Cell 2005
NPI-0052-101: Phase 1 study in Relapsed and
Relapsed, Refractory MM; Study Design
Phase 1, open-label, trial in pts with relapsed or relapsed/refractory
multiple myeloma (MM).
Dosing Regimen: 1-10 minute IV injection, D1, 8 and 15 in 4-wk cycles
Escalation: Accelerated Dose Titration
Dose escalation in 100% increments, until first drug related Grade 2 toxicity, thereafter
dose increments of 50% increments in cohorts of at least 3 pts.
Cohorts expanded to 6 pts if DLT reported.
RP2D cohort of 12 pts
Transition to new lyophile formulation (lyophile with ~1/2 excipient volume of original liquid
formulation).
Subset of intra-pt lyophile-liquid cross-over with comparative PK.
PK: Cycle 1, D1 & D15.
PD: Baseline: Cycle 1, D1 &15 and Day 15 every even cycle thereafter.
Key Inclusion Criteria
Karnofsky Performance Status (KPS) 70%.
Relapsed or relapsed/refractory MM for which no other approved
treatment is available and clinically indicated.
All Adverse Events resulting from prior chemotherapy, surgery, or
radiotherapy, must have resolved to CTCAE (v. 3.0) Grade 1 .
Labs
Hemoglobin 8 g/dL
Absolute Neutrophil Count 1.0 x 109 /L
Platelet count 50 x 109 /L
Serum bilirubin 1.5 x ULN
AST 2.5 x ULN
Serum creatinine ULN
Creatinine clearance 50 mL/min
Key Exclusion Criteria
Prior therapy within 28 days
> Grade 1 proteinuria, untreated UTI, or pre-existing kidney disease
Mucosal or internal bleeding and/or platelet refractory
Hypersensitivity CTCAE Grade 3 to propylene glycol or ethanol
Pregnant or breast-feeding
Clinically significant co-morbid disease:
Active uncontrolled infection
Significant cardiac disease
Ongoing coagulopathies
Demographics
Patients (N=32)
Median age (years)
61
Male/Female
20 / 12
KPS 80 -100
27
70
4
Myeloma Subtype
Heavy Chain 17 IgG (53%)
7 IgA (21%)
Light Chain
17 kappa (53%)
7 lambda (21%)
Oligo-/Non-secretory 6 (19%)
Time from Initial Diagnosis (years)
5.5 (1.5 14.3)
Number of Prior Regimens (median)
5 (1 11)
Prior SCT
20 (62%); 4 with >1 SCT (12%)
Prior Bortezomib
21 (66%)
Refractory to Prior Bortezomib*
11 (34%)
*No response on prior bortezomib-containing regimen OR
progression on or within 60 days of last dose of bortezomib
Enrollment
Cohort
Dose (mg/m2)
# Patients
1
0.025
3
2
0.075
1
3
0.050
3
4
0.075
6
50.15
2
60.30
1
70.60
3
80.70
8
9
0.70 (Lyophile)
5
Adverse Events 10%
0.025 mg/m2
0.05 mg/m2
0.075 mg/m2
0.15 mg/m2
0.3 mg/m2
0.6 mg/m2
0.7 mg/m2
Adverse Event >10% of
(n=3)
(n=3)
(n=7)
(n=2)
(n=1)
(n=3)
(n=13)
Patients
Grade Grade Grade Grade Grade Grade Grade Grade Grade Grade Grade Grade Grade Grade
1-2
3-4
1-2
3-4
1-2
3-4
1-2
3-4
1-2
3-4
1-2
3-4
1-2
3
Nausea
12
1
1
5
3*
Fatigue
213
1
5
1
Headache
21
1
7
Diarrhoea
11
1
3
1
Vomiting
11
1
31
Dizziness
11
1
4
Constipation
11
1
2
Back Pain
12
1
1
Anorexia
1
4
Dyspnoea
12
11
1
Upper repiratory tract
111
11
infection
Shoulder Pain
11
1
1
As of 06 Nov 2009
*without prophylaxis
NPI-0052 Phase I Trials Summary, including 101
Proteasome Inhibition (CT-L inhibition, packed whole blood)
Activity
CT-L
20S
PWB
Inhibition%
Consolidated results from clinical trials NPI-0052-100, NPI-0052-101 and NPI-0052-102
14
Pharmacokinetics: Summary
Dose related increases for Cmax and AUCtotal
Short half-life, mean < 10-15 mins
Large volume of distribution
Rapid clearance
Rapid (1-2 mins) distribution from blood into organs
and tissues, including tumor
15
Pharmacokinetics: Preliminary
Comparison of Formulations (liquid vs. lyophile)
Subset with intra-pt cross-over comparison between
liquid and lyophile formulations
0.7 mg/m2 NPI-0052
Sequence alternating between pts
No appreciable difference between the liquid and
lyophile formulations for PK parameters
T1/2
C
AUC
Clearance
Vss
MAX
TOTAL
Min
ng/mL
ng/mL*min
L/min
L
Liq
Lyo
Liq
Lyo
Liq
Lyo
Liq
Lyo
Liq
Lyo
7.7
6.8
66.8
56.4
442.9 461.3 3.45
3.23
39.6
31.1
Data expressed as Mean of 2 pts
16
NPI-0052
Paraprotein-Protein Best Response (n=31)
Best Response by EBMT(modified); 18/31 (58%) SD
SD > 6 mos in 9 pts (28%)
13/31 (42%) PD
Patient 003-056
0.15 mg/m2
Patient 003-056 62 yr gentleman, diagnosed in June 1998 (IgG); bortezomib responsive
12/98 03/99
Vincristine, Adriamycin, Dexamethasone (PD)
10/01 03/04
2-methoxyestradiol (SD)
04/99 05/99
High dose Cyclophosphamide (PD)
04/04 03/08
Lenalidomide (PR)
01/00 06/00
Thalidomide (PR)
07/08 Present
NPI-0052 (0.6 mg/m2) (SD)
Starting dose: 0.075 mg/m2
08/00 10/00
Alpha-interferon (PD)
Dose escalations: 0.15 mg/m2 in Cycle 7
0.3 mg/m2 in Cycle 8
11/00 12/00
Rituximab (PD)
0.6 mg/m2 in Cycle 9
02/01 08/01
Bortezomib, Dexamethasone (MR)
Patient continuing on study.
Conclusions/ Future Directions
Escalation to the RP2D (0.7 mg/m2) in MM pts was accomplished in this study
Assessment of this dose continues with the recently introduced lyophile formulation
The trial will be amended to include twice weekly dosing
NPI-0052 generally well tolerated at doses below the MTD
Common AEs: fatigue, nausea/vomiting, dizziness, headache
Preliminary indications that the new formulation is better tolerated
NPI-0052 does not induce neuropathy, neutropenia or thrombocytopenia
Preliminary PK data suggest dose dependence exposure, short elimination half life,
rapid clearance, large volume of distribution
Across all studies performed with NPI-0052:
Inhibition is dose and time dependent
Inhibition reaches or exceeds that obtained with efficacious doses of bortezomib without its
adverse event profile
Clinical activity suggested by decreases in para-protein and durable SD (> 6 months)
in 28% (9/31) pts
66% received prior bortezomib (34% refractory to bortezomib)
NPI-0052 continues to be assessed in MM, lymphoma, leukemia and solid tumors, wkly
and twice-wkly, alone and in combination
Study NPI-0052-102 (Presented Sunday, December 6, 2009 Poster #II-669)
Acknowledgements
A special thanks to the patients and their families who participated in this study.
We would also like to acknowledge the support of all the individuals
that contributed to the study at the participating institutions:
Nora Loughney
Dana Farber Cancer Institute, Boston, MA
Deborah Doss
Buffy Jansak
The Ohio State University Comprehensive
Mindy Bowers
Cancer Center,
Columbus, OH
Colleen Harvey
University of Michigan,
Ann Arbor, MI
Monica Mitchell
University of Chicago,
Angela Cisneros
Chicago, IL
Amanda Sanders
Winship Cancer Institute,
Atlanta, GA
Amy Whitworth
Roswell Park Cancer Institute, Buffalo, NY
Sandra Wear
Multiple Myeloma Research Consortium,
Norwalk, CT
Ana Lay
Nereus Pharmaceuticals, Inc., San Diego, CA