Transcript Slide 1

A phase I dose-escalation study of
LDE225, a Smoothened (Smo)
antagonist, in patients with
advanced solid tumors
J Rodon1, J Baselga,1 HA Tawbi,2 Y Shou,3
C Granvil,3 J Dey,3 MM Mita,4 AL Thomas,5 DD Amakye,3
AC Mita4
1Vall
d’Hebron University Hospital, Barcelona, Spain; 2University of Pittsburgh Cancer
Institute, Pittsburgh, PA; 3Novartis Pharmaceuticals Corporation, East Hanover, NJ;
4Cancer Therapy & Research Center, San Antonio, TX; 5Leicester Royal Infirmary,
Leicester, UK
Scientific rationale: the Hedgehog (Hh)
signal transduction pathway
Shh
Shh Shh
Shh
ShhShh
Shh Shh
Shh
Ptc1
Smo
Smo
GLI
Ptc1
g
Smo
g
b
b
GLI
PI3K
PDK
PKB
Gli1
Cellular
proliferation,
differentiation
and survival
Sufu
HIP, PDGFR,
Gli, Cyclin D1,
N-myc, Wnt
mRNAs
AAAAA
MIM
CBP/p300
Gli1/2
Gli3
Gli, glioma-associated oncogene homolog zinc finger protein
Gli2
Sufu
MIM
Gli3
Scientific rationale: the Hedgehog (Hh)
signal transduction pathway
Shh
Shh Shh
Shh
ShhShh
Shh Shh
Shh
BCC
BCC
Medulloblastoma
Ptc1
Smo
Smo
GLI
Smo
Ptc1
g
g
b
b
GLI
PI3K
Basal Cell
Carcinoma (BCC)
PDK
Hh activation in 70%
of cases
Pancreatic cancer
Colon cancer
Lymphoma
PKB
Gli1
Sufu
MIM
Gli2
Sufu
Gli3
MIM
SCLC
CML
Pancreatic cancer
Breast cancer
Tumorigenesis of several human cancers caused by different mechanisms:
– Genetic:
•
•
Inactivating mutations in Patched (Ptch) or Suppressor of Fused (SuFu) protein
Activating mutations in Smo
– Autocrine
– Paracrine
•
Aberrant activation of the Hh pathway (tumor or stem cells)
LDE225 – a potent and selective Smo
antagonist
• LDE225 is a novel oral inhibitor of Smo
– Structurally distinct from steroidal alkaloids such as cyclopamine
O
H
CF3
N
H
O H
H
H
N
H
H
HO
O
N
N
O
Cyclopamine
LDE225
LDE225 – preclinical summary
Ptch +/-, p53 -/- MB model
Gli-1 mRNA (human)
Luciferase (mouse)
Tumor volume (mm3)
mean ± SEM
3000
LDE225
Vehicle
2500
5mg/kg
2000
1500
1000
500
10 mg/kg
20 mg/kg
0
Gli-1 promoter
8
Assay
Cell line
IC50(nM)
Shh-induced
Gli-1 mRNA
Human HEPM
13
Shh-induced
Gli-1 Luciferase
Mouse TM3
7
10 12 14 16 18 20 22
Days post-implantation
LDE225 is a novel oral inhibitor of
Smo that potently inhibits Smodependent proliferation in vivo in
preclinical studies
Gli, glioma-associated oncogene homolog zinc finger protein; Shh, Sonic Hedgehog
8 NBCCS patients
27 BCC patients
10 12 14
8
6
4
2
Complete response
Partial response
No response
0
• Germ line mutations in Ptch,
leading to subsequent
development of multiple BCCs
Cumulative number of tumors
Topical LDE225 (0.75%) in Naevoid Basal
Cell Carcinoma Syndrome (Gorlin Syndrome)
LDE225
Vehicle
n=13 LDE225 cream (BID)
n=14 Vehicle
• Established proof of concept
• Orphan drug status granted in EU for
BCC in Gorlin Syndrome
De Rie MA, et al. Society for Investigative Dermatology (SID) 2010
Baseline
After 4 weeks
Phase I study design (oral formulation)
• Primary
– Determination of MTD and/or optimal biologic dose,
characterization of DLTs of oral LDE225 administered on a daily
continuous schedule
• Secondary
– Safety and tolerability of LDE225
– Pharmacokinetic profile
• 7-day PK run-in period to characterize the PK profile of LDE225
following a single oral dose
• Days 1, 8, 15 and 28 in Cycle 1
– Biomarker and pharmacodynamic assessments: effect on
markers of Hh signaling pathway (Gli-1 expression by RT-PCR)
– 18FDG-PET for metabolic anti-tumor activity
– Overall response as per RECIST
LDE225 Phase I: study design
Phase IA, multicenter, open-label, single-agent, dose-escalation
study in patients with advanced solid tumors
Dose-escalation phase
Bayesian logistic regression model using
overdose control
MTD expansion
phase
Declaration
of MTD*
Dose levels
Decision to dose escalate based on
review of toxicities in Cycle 1 and other
clinical, PK, and laboratory data
*Defined
Oral, daily LDE225,
28-day cycle
• Advanced solid tumor – including locally
advanced, multifocal or metastatic basal cell
carcinoma (BCC), and recurrent
medulloblastoma (MB)
• Age 18 years or older, WHO performance
status ≤2, and other standard Phase I inclusion
criteria
as the highest drug dosage not causing DLT in >33% of patients during the first treatment cycle
Baseline cohort characteristics
Dose-level (continuous QD)
100 mg
(N=6)
200 mg
(N=6)
400 mg
(N=5)
800 mg
(N=11)
1500 mg
(N=7)
Total
(N=35)
Age (mean, years)
43.2
52.2
54.2
61.6
48.9
53.2
Gender (male, %)
33.3
50.0
60.0
72.7
28.6
51.4
0
1
1
0
4
0
0
1
1
4
3
1
0
0
1
4
3
0
0
4
2
0
1
1
3
9
5
3
2
16
Primary site of cancer (n)
Pancreas
Lung
Medulloblastoma
Breast
Others (n≤1)*
Most common grade 1–2 AEs potentially
related to LDE225 treatment
Dose-level (continuous QD)
100 mg
(N=6)
200 mg
(N=6)
400 mg
(N=5)
800 mg
(N=11)
1500 mg
(N=7)
Total (n,%)
(N=35)
Nausea
3
1
1
1
2
8 (22.9)
Anorexia
2
1
1
0
0
4 (11.4)
Vomiting
1
1
0
0
0
2 (5.7)
Dysgeusia
0
1
0
0
1
2 (5.7)
Muscle spasms or myalgia
Myalgia
2
0
2
1
0
0
0
0
2
1
6 (17.1)
2 (5.7)
Fatigue/asthenia
5
2
0
0
0
7 (20.0)
Headache
1
1
1
0
1
4 (11.4)
Lethargy
0
0
0
2
0
2 (5.7)
Hyperbilirubinemia
0
2
0
0
0
2 (5.7)
Rash
0
0
0
2
0
2 (5.7)
Drug-related AE (n)
GI Toxicity
AEs with total incidence of ≥2 represented; cut-off date 24 May 2010
Pharmacokinetic profile after a single dose
(7-day run-in)
Mean effective half-life ~90 h (range: 23–230 h)
Median time to reach Cmax was 4 h (range: 1–48 h)
Steady state conditions achieved between Days 15–22
LDE225 plasma conc. (nM)
10000
1000
100
100 mg QD (n=6)
200 mg QD (n=6)
400 mg QD (n=5)
800 mg QD (n=11)
1500 mg QD (n=7)
10
1
0
24
48
72
96
Time (h)
120 144
168
PK: relationship between LDE225 dose and
plasma exposure (Cmax and AUC) at Day 15
Plasma AUC0-24 (nM*hr)
Plasma Cmax (nM)
4000
• Dose-proportional systemic
exposure up to 1500 mg/day
(R2=0.6019 P=0.0001)
Cmax Day 15
3000
2000
• Two-fold increase in Cmax and
five-fold increase in AUC on Day 15
versus Day 1
1000
0
80000
AUC0-24 Day 15
• Target exposure (AUC) as predicted
by preclinical models was achieved
by Day 15 at doses ≥400 mg daily
60000
40000
Target
exposure
20000
0
100
200
400
800
Dose (mg/day)
1500
• Variability in exposure was
moderate–high (CV%) in AUC
(43–104%) and Cmax (38–90%)
Biomarkers: LDE225-induced changes in
skin Gli-1 mRNA expression after 28 days
Mean Fold Change –1.14
–3.17
–7.36
–3.56
–19.14
Mean % inhibition 12.3%
5
68.4%
86.4%
72.0%
94.8%
Fold-change from baseline
0
-5
–10
–15
–20
–25
–30
100 mg
200 mg
400 mg
800 mg
1500 mg
–35
Patients
Skin Gli-1 Reduction (DCt)
Reduction in Gli-1 expression observed
in skin correlated with plasma exposure
.. ..
.. ... .
..
...
Cmax (nM) Day 15
0
–2
–4
0
1000
2000
....
....
.. ... .
......
.. .. . .. .... . .
.
.
Cmin (nM) Day 15
3000
0
1000
2000
AUC24 (nM*h) Day 15
3000
PK measurement value
0
20000
40000
Cohort 1; 100 mg
Cohort 2; 200 mg
Cohort 3; 400 mg
Cohort 4; 800 mg
Cohort 5; 1500 mg
CT, threshold cycle by RT-PCR analysis
60000
Summary of anti-tumor activity (n = 31)
• One patient (medulloblastoma, 200 mg/day) achieved
an objective partial response (PR)
• One partial metabolic response in a second patient with
medulloblastoma
• Six patients (2 NSCLC, basal cell carcinoma, spindle
cell carcinoma, osteocarcinoma and breast cancer)
have received LDE225 for more than 4 months
LDE225 is active in medulloblastoma
Patient A (200 mg)
Prior surgery, radiation, 4
chemotherapy regimens
and autologous BMT
Partial response following
2 cycles of therapy
A
Patient B (1500 mg)
Pre-treatment
Baseline
Cycle 2 Day 28
MRI
C2D28
Prior surgery, radiation, 4
chemotherapy regimens
and autologous BMT
Partial metabolic
response following 2
cycles of therapy
B
FDG-PET, fluorodeoxyglucose-positron emission tomography
Conclusions
• LDE225 is generally well tolerated at doses of
100–1500 mg daily
– No DLTs to date
• LDE 225 has demonstrated a favorable PK profile, with
dose-proportional exposure up to 1500 mg daily
• Exposure-dependent target inhibition was observed
– Up to 95% Gli-1 reduction in skin
• Anti-tumor activity was observed across a wide
therapeutic dose range
• Dose escalation is ongoing to establish a
recommended dose and schedule for future studies
Acknowledgements
• Patients who took part in this trial and their families
• All staff at the following study sites:
– Vall d’Hebron University Hospital: Marta Beltran, Gemma Sala
– University of Pittsburgh Cancer Institute: Kathleen Kovalik,
Andrea Yartin
– Cancer Therapy & Research Center in San Antonio: Patricia
O'Rourke, Hope Moreno, Celina Herrera
– Leicester Royal Infirmary, UK: Rahima Ibrahim, Samantha
Baker, Kate Sorrell
– University Hospital of Zurich, Switzerland: Prof. Reinhard
Dummer, Dr. Sharon Gobbi, Severine Buffoni, Gionata Cavadini
• Novartis LDE225 Research and Development Team
• Special acknowledgement to: Kathleen Roberge, Novartis
Clinical Trial Leader