NPI-0052-101
Phase 1 Clinical Trial of NPI-0052 in
Patients with Relapsed or
Relapsed/Refractory Multiple
Myeloma
Craig Hofmeister MD, Andrzej Jakubowiak MD PhD,Todd Zimmerman MD,
Alison Hannah MD, Matthew A. Spear MD,
Asher Chanan Khan MD, Michael A. Palladino PhD,
Saskia T.C. Neuteboom PhD, G Kenneth Lloyd PhD,
Angie Longenecker RN, Susan Kelley MD, Gillian Cropp MSc,
Kenneth Anderson MD, Paul Richardson MD
Ohio State University, Columbus, OH
University of Michigan, Ann Arbor, MI
University of Chicago, Chicago, IL
Roswell Park Cancer Institute, Buffalo, NY
Dana Farber Cancer Institute, Boston, MA
Multiple Myeloma Research Consortium, Norwalk, CT
Nereus Pharmaceuticals, Inc., San Diego, CA
NPI-0052
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BACKGROUND
NPI-0052
Novel second generation 20S proteasome inhibitor (non-peptide based)
Unique proteasome inhibition profile:
Fast, high 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 tumors resistant to bortezomib
NPI-0052
Proteasome Inhibition Profile
1 mg/kg Bor tez omib, IV
0.15 mg/kg N PI-0052, IV
10 0
10 0
ty
tivity
tivi
he
the
75
t
75
of
of
n-likeac
*
tion
**
tion
in-likeac
50
50
bi
bi
inhi
ryps
inhi
ot
otrypsi
25
%
25
%
ym
chym
ch
0
0
1.5 hr
2 4 hr
4 8 h r
72 hr
168 hr
1.5 hr
24 hr
48 hr
72 hr
1 68 hr
Time
Time
0.15 mg/kg NP I-0052, IV
1 mg/kg B ortez omib, IV
10 0
0
he
he
t
75
tivity
t
tivity
of
of
-3 0
tion
likeac
50
tion
likeac
*
n-
*
n-
inhibi
inhibi
-6 0
25
%
trypsi
%
trypsi
0
-9 0
1.5 hr
24 hr
48 hr
72 hr
1 68 hr
1 .5 hr
24 hr
48 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
100
ty
the
he
tivity
75
t
tivi
75
of
of
tion
50
tion
likeac
50
e-likeac
bi
*
inhibi
inhi
*
%
spas
25
25
%
ca
caspase-
0
0
1.5 hr
24 hr
48 hr
72 hr
168 hr
1.5 hr
24 hr
48 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 patients refractory
MM cells from patients 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 was administered orally BIW for 13 weeks
NPI-0052 is well tolerated and prolongs survival with significantly reduced
tumor recurrence
Similar reduced tumor recurrence is obtained with NPI-0052 administered IV
6
Chauhan et al., Cancer Cell 2005, 8(5):407-419
NPI-0052 Exhibits a Large Therapeutic Index
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 were treated for 48h.
7
Chauhan et al., Cancer Cell 2005
NPI-0052-101
METHODS
Study design
Phase 1, open-label, trial in patients with relapsed or relapsed/refractory
multiple myeloma.
Dosing Regimen: 10-minute IV injection, Days 1, 8 and 15 in 4-week cycles
Escalation: Accelerated Dose Titration
­ Dose escalation in 100% increments, until the first drug related Grade
2 toxicity, thereafter dose increments of 50% increments in cohorts of
at least 3 patients.
­ Cohorts are expanded to 6 patients if a DLT is reported.
RP2D cohort of 12 patients
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 1.5 x 109 /L
Platelet count 75 x 109 /L
Serum bilirubin 1.5 x ULN
AST 2.5 ULN
Serum creatinine and BUN ULN.
Creatinine clearance 60 mL/min
Lipase and amylase ULN
Key Exclusion Criteria
Prior therapy within 28 days
> Grade 1 proteinuria, untreated UTI, or active sediment
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.
Adrenocortical insufficiency
Acute or chronic pancreatitis.
Ongoing coagulopathies.
NPI-0052-101
RESULTS
Demographics
Patients (N=24)
Median age (years)
60.5
Male/Female
14 / 10
KPS 80 -100
21
70
3
Myeloma Subtype
Heavy Chain 13 IgG (54%)
4 IgA (17%)
Light Chain
10 kappa (42%)
7 lambda (25%)
Oligo-/Non-secretory 6 (29%)
Time from Initial Diagnosis (years)
5.5 (1.5 ­ 14.3)
Number of Prior Regimens (median)
4 (1 ­ 9)
Prior SCT
17 (71%); 4 with >1 SCT (17%)
Prior Bortezomib
16 (67%)
Refractory to Prior Bortezomib*
7 (29%)
*No response on prior bortezomib-containing regimen OR
progression on or within 60 days of last dose of bortezomib
Enrollment
Cohort
Dose
# Patients # Pts with
DLT
(mg/m2)
DLT
1
0.025
3
0
0
2
0.075
1
1
Acute renal failure
(reversible)
3
0.050
3
0
0
4
0.075
6
0
0
5
0.150
2
0
0
6
0.300
1
0
0
7
0.600
3
0
0
8
0.700
5
1
Fatigue
(reversible)
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=5)
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
3-4
Nausea
1
2
1
3
1
Vomiting
1
1
1
2
1
Constipation
1
1
1
Diarrhea
1
1
1
Fatigue
2
1
3
1
2
1
Headache
2
1
3
Dizziness
1
1
1
Back Pain
1
2
1
1
Pain in extremity
2
1
Upper Respiratory
11
1
2
Tract Infection
Dyspnea
1
2
As of 12 May 2009.
Patient #006-031
01/09 (2 cycles)
Start of NPI-0052
11/08-12/08 OSU
Velcade/Doxil/Dex
07034 Anti-KIR human
Patient remains active on-study
(partial response)
monoclonal Antibody
(progressive disease)
Cycle 3 =531 (-71%)
Patient 006-031: 50yo male, diagnosed in January 2004 (IgA); bortezomib-sensitivity unknown.
01/04 - 10/06
Doxil, Vincristine, Dexamethasone and Revlimid (CRu)
01/07 ­ 03/07
Velcade and Dexamethasone (CRu);
04/08 and 08/08 Tandem autologous stem cell transplant;
08/08 ­ 10/08
Prednisone (palliative);
11/08 - 12/08
OSU 07034 Anti-KIR human monoclonal Antibody (PD);
01/09 ­ 01/09
Velcade, Doxil, Dexamethasone (PR); Discontinued due to intolerability.
03/-09- present
NPI-0052 (0.7 mg/m2) (PR on 04 May 09)
Patient #007-002
Cycle 1
Cycle 1
Cycle 2
Patient 007-002: 81 yo female, diagnosed in February 2003 (IgA; chromosome 13 deletion). Bortezomib-sensitivity unknown.
05/05 - 05/06
Doxil, Velcade, Dexamethasone (PR)
06/06 ­ 04/07 Perifosine, Dexamethasone (MR);
04/07 ­ 05/08 Revlimid, Velcade, Dexamethasone (PR);
05/08 ­ 10/08 Melphalan, Prednisone, Revlimid (SD);
03/09-present NPI-0052 (0.7 mg/m2., dose reduced to 0.6 mg/m2 due to Grade 3 fatigue)
Clinical Benefit (Stable Disease)
Pt #
Dose
Months
Prior
M-Protein
Outcome
Prior Therapy
(mg/m2)
on
Bortezomib
Best
Study
Response
(% Change)
003-052
0.025-0.05
12
No
-15
SD
Thal/Dex 11 Months
AutoSCT
(5 month remission)
003-051
0.025
5
Yes
-9
SD
Bortezomib/Dex
(BZ-refractory)
6 Months
003-056
0.075-0.6
11+
Yes
-7
SD/Active
Lenalidomide 48 Months
(BZ-sensitive)
006-128
0.075-0.6
8+
No
-1
SD/Active
Lenalidomide/
Temsirolimus 5 Months
003-053
0.05
8
No
0
SD
Tanespimycin 6 Months
006-127
0.075-0.6
6
No
8
SD
VAD 2 Months
AutoSCT
(5 year remission)
Pharmacokinetics
Dose related increases for Cmax and AUCtotal
Short half-life, mean < 10-15 minutes
Large volume of distribution
Rapid clearance
Rapid (1-2 min) distribution from blood into organs and
tissues, including tumor
19
NPI-0052 Phase I Trials Summary
Proteasome Inhibition (CT-L in PWB)
#
#
*
*
Activity
*
CT-L
20S
PWB
Inhibition%
Consolidated results from clinical trials NPI-0052-100, NPI-0052-101 and NPI-0052-102
PWB: Packed Whole Blood
20
Conclusions
Escalation to the MTD (0.7 mg/m2) determined in two phase 1 trials
in solid tumor/lymphoma/leukemia patients was accomplished in
this study (~20 patients treated at this dose).
DLTs in other studies were transient unsteady gait and hallucinations
(principally closed-eye visuals; seeing images when eyes closed).
Enrollment continues at 0.7 mg/m2 in this study.
Grade 3 fatigue was observed in one patient (reversible and not seen
upon re-challenge at 0.6 mg/m2 in this 81 year old patient).
Grade 3 emesis was observed in one patient (duration 1-2 days).
Emesis did not recur upon subsequent re-challenge with anti-emetic
prophylaxis.
NPI-0052 was generally tolerable at 0.7 mg/m2
Common AEs: fatigue, nausea/vomiting, dizziness, headache.
Reversible, transient, closed-eye visuals and affect changes have
been reported at low incidence.
NPI-0052 does not appear to induce neuropathy, neutropenia or
thrombocytopenia.
Conclusions
Clinical benefit is evidenced by decreases in M-Protein, with a
significant proportion having failed bortezomib therapy.
Prolonged SD has been seen even at low doses.
Convenient weekly dosing (Days 1, 8 and 15 every 4 weeks)
Preliminary PK data indicate dose dependence exposure, short
elimination half life, rapid clearance and large volume of
distribution.
Across all studies performed with NPI-0052, inhibition of
proteasome activity into the predicted minimum effective range
has been seen at doses 0.15 mg/m2. Inhibition is dose and time
dependent, and reaches or exceeds that obtained with efficacious
doses of bortezomib without producing the adverse event profile
reported with bortezomib, suggesting a therapeutic ratio
potentially in the range of 2-6 fold.
Enrollment continues to further refine these initial results, as well
as assess an alternate formulation.
Acknowledgements
A special thanks to the patients that 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:
Katie Loftus
Desmond McDonnell
Deborah Doss
Buffy Jansak
Ana Lay
Theodore Ghazal
Anne Kopko
Colleen Harvey
Sandra Wear
Charles Leister
Monica Mitchell
Angela Cisneros
Amy Whitworth
Dana Farber Cancer Institute, Boston, MA
Ohio State University, Columbus, OH
University of Michigan, Ann Arbor, MI
University of Chicago, Chicago, IL
Roswell Park Cancer Institute, Buffalo, NY
Multiple Myeloma Research Consortium, Norwalk, CT
Nereus Pharmaceuticals, Inc., San Diego, CA