Phase Ib Study of Oral Panobinostat (LBH589) +
IV Bortezomib in Patients (Pts) With
W
Wit
Wi h Relapsed
Relapsed
(Rel) or Rel and Refractory (Ref) Multiple Myeloma
(MM)
Jù
Jesùs F. San-Mi
l1
guel , Oh
Orhan S
2
Sezer , Di
Dav d
id Si
Si
l3
egel , Ad
Andreas G
t
uen h 4
ther ,
Joan Bladé5, Ian Prosser6, Bourras R. Bengoudifa7, Martin Klebsattel7, Priscille M.
Bourquelot7, Kenneth C. Anderson8
1Hospital Universitario de
de Salamanca
Salamanca, Salamanca
Salamanca, Spain; 2
Spain; Hematology and Oncology
Oncology, Wuerzburg
W
University
University Hospital
Hospital,
Wuerzburg, Germany; 3Hackensack University Medical Center, Hackensack, NJ, USA; 4Medical Department II, Div.
Stem Cell Transplantation and Immunotherapy, University of Kiel, Kiel, Germany; 5Hospital Clinic de Barcelona,
Barcelona, Spain; 6The Canberra Hospital, Canberra, Australia; 7Novartis Pharma AG, Basel, Switzerland; 8Dana-
Farber Cancer Institute, Boston, MA; Multiple Myeloma Research Consortium
San-Miguel JF, et al. American Society of Clinical Oncology (ASCO) (June 4-8, 2010), Chicago,
IL, USA. [Abstract 8001].
(NCT00532389)
Multiple Myeloma - Introduction
86,000 new cases of MM in 2002 worldwide1
~0.8% of all cancers, 2nd most frequent hematologic malignancy
In the US, there will have been an estimated 20,500 new cases of
MM and 10,500 MM-related deaths in 20092
Novel agents (thalidomide, lenalidomide, bortezomib) have
contributed to improving the outcome of pts with MM in recent
years3
Despite initial response, almost all pts relapse and then become
refractory to subsequent regimens
Refractory MM to both bortezomib and thalidomide/lenalidomide is
associated with a very poor prognosis
Median survival < 3 months4
1. Parkin DM, et al. CA Cancer J Clin 2005;55:74108.
2. Jemal et al. CA Cancer J Clin 2009;59: 225-249.
3. Kumar SK, et al. Blood. 2008;111:25162520.
4. Kumar S, et al. ASH 2009. Abstract 2878.
Target Proteins of DACs
Increased Protein Acetylation
Panobinostat is an oral pan-
deacetylase inhibitor (pan-
DACi) that increases
acetylation of proteins
HDAC
involved in multiple
1,3
oncogenic pathways
HDAC
HDAC
6
HDAC
Panobinostat causes
1,2,3
sustained effects on proteins
p53
involved in cell cycle
Increased
regulation, gene
apoptosis
pp
transcription, angiogenesis,
HSP90
and tumor cell survival
Inhibition of
Histones
unfolded protein
Tumor
response and
Panobinostat is a potent
suppressors
tumor cell
pan-
pan DACi, with low
Aggresomes
proliferation
HIF-1
nanomolar activity against all
Decreased Tumor
Decreased
cell survival
class I, II, and IV HDAC
angiogenesis
enzymes
Prince HM et al. Future Oncol. 2009.
Blockade of Ubiquinated Protein Catabolism
Protein
Ub
Ub
protein aggregates
aggregates
(toxic)
Ub
Ub
Ub
Ub
26S proteasome
HDAC6
Bortezomib
Ub
Ub
panobinostat
HDAC6
dynein
Ub
Ub
Lysosome
y
Aggresome
HDAC6
Ub Ub
dynein
Ub Ub
Ub
Ub
Microtubule
At
Aut
h
op agy
Hideshima et al, Clin Cancer Res;2005; 11: 8530
Catley et al, Blood 2006; 108: 3441-9.
Preclinical Anti-MM Efficacy of Panobinostat
Synergistic activity in combination with bortezomib and dexamethasone
PAN single-agent
PAN + BTZ
PAN + BTZ and DEX
RPMI Cells
MM.1S Cells
o
vitrIn
PAN + BTZ + DEX Synergistically
PAN Reduces Bone Density Loss
Inhibits Tumor
Tumor Growth
Growth
MM.1S Cells
vivoIn
Catley, Blood, 2006.
BTZ, bortezomib; DEX,
Ocio, Hematologica, 2010.
dexamethasone; PAN, panobinostat.
Single-Agent Panobinostat in MM
Summary of Results of ALPHA MM Phase II / LBH589B2203
Perspectives
38 pts: all refractory on most recent therapy
Prior lines of therapy: 5 (range
g 2-12)
25 out of 38 pts had received all 3 recent agents, bortezomib ,
lenalidomide, and thalidomide, and 31 at least bortezomib and
one IMiD
Single-agent dose of 20 mg three times a week, QW suboptimal,
however:
Interesting observations of activity:
· 1 VGPR and 1 MR
· Both pts remained stable on panobinostat for > 15 months
Tolerability:
· Only few discontinuations due to AEs (cytopenia, GI, fatigue)
· Few QTc interval prolongations, not clinically significant
Efficacy did not meet protocol defined criteria to open Stage 2, but
key strategic focus: combinations, as guided by preclinical data
Panobinostat Bortezomib in Rel or Rel & Ref MM pts
Dose Escalation Phase of LBH589B2207 Study - Treatment
T
Scheme
3 week cycles
Week
W
1
Week
W
2
Week
W
3
8 Cycles with
PAN
D1
D3
D5
D8
D10
D12
D15
D17
D19
BTZ +PAN
TIW QW
BTZ
D1
D4
D8
D11
PA
PAN every week
week
schedule &
Dex
D1 D2
D4 D5
D8 D9
D11 D12
continued until
progression
TIW QW:
QW three times a week, every week
Drug dose levels used in dose escalation phase
PAN: 10 mg, 20 mg, 25 mg, and 30 mg
BTZ: 1.0 mg/m2, 1.3 mg/m2
(Dex : 20 mg fixed dose added at Cycle 2 in suboptimal responders)
Pi
Pts with MM
MM
l
re
d
apse
f
a ter 1l
1 iline f
o therapy, or
l
re
d
apse
d
an
f
re ractory,
and suitable for treatment with BTZ
Panobinostat +Bortezomib in Rel or Rel & Ref MM pts
Patients' Characteristics
Characteristics
Number of Pts (N = 47)
Median age, years (range)
62 (46-83)
Age category, < 65/ 65
32/15
Gender, M/F
32/15
Myeloma subtype
subtype, % IgG / IgA / LC
26/11
26/1 /22
ECOG performance status 0, 1, 2
22/25/0
Prior lines of therapy, median (range)
2 (1-10)
Prior stem-cell transplant
36
Prior BTZ / refractory to BTZ
28/15
Prior BTZ + IMiD
22
Disease status at entry (Rel / Rel & Ref)
24/22
Panobinostat Bortezomib in Rel or Rel & Ref MM
Determination of MTD
MTD declared: panobinostat 20 mg + bortezomib 1.3 mg/m2
Cohorts 3 and 6: 3 DLTs out of 17 evaluable pts observed
Dose limiting toxicity
toxicity (DLT)
(DLT) by treatment cohort (Co)
Co. 1
Co. 2
Co. 3
Co. 4
Co. 5
Co. 6
n = 7
n = 7
n = 8
n = 7
n = 9
n = 9
PAN
PA
10
20
20
30
25
20
(mg)
BTZ
1.0
1.0
1.3
1.3
1.3
1.3
(mg/m2)
DLT
0/6
1/6
0/8
4/7
1/6
3/9
(pts/ev)a
1.Neutropenia
1.TCP
1.TCP
1.Gastric hemorrhage
2.Pi
/ asthenia
Pneumonia
asthenia
2.Ot
Or h
thost t
a itic
/ TCP
/ dizziness
hypotension
DLTs
--
/ neutropenia
(per pt)
3.Neutropenia /
3.Fatigue
vomiting
4.TCP
a Number of patients meeting DLT criteria out of patients evaluable for DLT determination.
TCP, thrombocytopenia.
Panobinostat + Bortezomib Safety
Incidence of Hematologic AEs
AEs in 5 (>10%) pts, regardless of causalitya
AE
% All Grades
% Grade 3/4
(preferred term)
Thrombocytopenia
89
81
Neutropenia
70
57
Ai
Anemia
59
21
Leukopenia
21
17
Thrombocytopenia was readily managed with dose modification
and/or platelet transfusions
Single patient
gp
with grade
g
3 gastric
g
hemorrhage (on aspirin)
a Data cut-off: 06-Apr-2010: all cycles, for 47 patients from all cohorts.
Panobinostat + Bortezomib Safety
Incidence of Non-hematologic AEs
AEs in 10 (>20%) pts, regardless of causalitya
AE
% All
% Grade 3/4
AE
% All
% Grade
(preferred
Grades
(continued)
Grades
3/4
term)
Diarrhea
64
8
Vomiting
34
6
Nausea
55
4
Resp. tract infection
infection
23
11
Pyrexia
51
6
Hypokalaemia
23
8
Asthenia
42
25
Dizziness
23
4
Fatigue
42
8
Constipation
23
0
Decreased
36
2
appetite
Most of the gastrointestinal AEs were grade 1-2
Grade 3/4 neuropathy: 2 pts (4%), and pulmonary embolism 1 pt (2%)
No dose-related QTcF increase
a Data cut-off: 06-Apr-2010: all cycles, for 47 patients from all cohorts.
Panobinostat + Bortezomib Best Response
Dose Escalation B2207
B
B2207 Study in Relapsed MM Patients
Clinical benefit ( MR) in 13/17 (76%) at cohort 3 and 6 dose level
10
9
8
NA
7
tients
PD
Pa
6
SD
of
5
MR
4
PR
umber
VGPR
3
N
CR
2
1
0
Co. 1
Co. 2
Co. 3
Co. 4
Co. 5
Co. 6
PAN (mg)
10
20
20
30
25
20
BTZ (mg/m2) 1.0
1.0
1.3
1.3
1.3
1.3
PAN panobinostat; BTZ bortezomib.
CR, IF-negative CR; VGPR, very good PR; PR, partial response; MR, minor response; SD, stable disease; PD, progressive disease;
NA, no assessment.
Panobinostat + Bortezomib Efficacy
Responses Including Bortezomib-Refractory Patients
100
90
80
)
70%
%(
70
60%
60
MR
seRate
50
40
PR
Respon
30
VGPR
20
10
CR
0
All (N = 47)
BTZ refractory (n = 15)
Panobinostat + Bortezomib
Median Duration on Study
Cohort Dose Level
PAN + BTZ
(mg)
(g) (mg
(g/m2)
20 + 1.3
93 (24-176)
(Cohort 6)
25 + 1.3
129 (11-274)
(Cohort 5)
30 + 1.3
74 (11-442)
(Cohort 4)
20 + 1.3
95 (11-547)
(Cohort 3)
20 + 1.0
74 (7-424)
(Cohort 2)
10 +
1.0
44 (4-189)
(Cohort 1)
0
50
100
150
Days (range)
Duration on study was best at levels 20 mg/1.3 mg/m2 and
25 mg/1.3 mg/m2
Conclusions
Panobinostat orally TIW, every week, can safely be combined with
bortezomib at dose levels up to 20 mg and 1.3 mg/m2, respectively
Clinical benefit ( MR) was observed in 13 of 17 pts (76%)
treated at this dose level
Grade 3/4 thrombocytopenia was frequent and was manageable with
platelet transfusions and dose reductions
Combining panobinostat with bortezomib shows promising activity,
including in pts refractory to a prior bortezomib-containing regimen
70% response overall: 5 CRs + 3 VGPRs + 18 PRs + 7 MRs
(N = 47)
60% response in bortezomib-refractory pts: 6 PRs + 3MRs
(n = 15)
Future Directions
A large international randomized phase III trial of
bortezomib plus panobinostat vs bortezomib
(PANORAMA 1) in relapsed MM
In th
the US
US, a phase II trial of bortezomib plus
panobinostat (PANORAMA 2) in patients with
relapsed and bortezomib-refractory MM (Abstract
#TPS308, Monday AM)
Acknowledgments
Participating sites
To all current and future
Spain: Hospital
Italy: Università degli
patients
p
and their families
Ui
Universit
itario de
Sd
Stu i
di di
di Torino,
Salamanca; Hospital Clinic
Università di Bologna
All investigators and sites'
de Barcelona
study staff
Novartis global and
United States: Dana-Farber;
Australia: The
countries' teams
Hackensack, MMRC;
Canberra Hospital
Swedish Med
edica
c l
a Ce
C nt
e er
e
Germany: Universitatsklinikum
Canada: Vancouver General
Wurzburg; Universitat zu Kiel;
Hospital; Maisonneuve-
Universitaetsklinikum Leipzig
Rosemont Hospital