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DESCRIPTION
A phase I dose-escalation study of LDE225, a Smoothened (Smo) antagonist, in patients with advanced solid tumors. J Rodon 1 , 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 Mita 4 - PowerPoint PPT PresentationTRANSCRIPT
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A phase I dose-escalation study of LDE225, a Smoothened (Smo) antagonist, in patients with advanced solid tumorsJ 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
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ShhShh
ShhShh
Ptc1Smo
Gli1
Sufu
Gli2
Sufu
Gli3
MIM MIM
AAAAA
HIP, PDGFR,Gli, Cyclin D1,
N-myc, WntmRNAs
CBP/p300
Gli1/2 Gli3
GLI
ShhShh
GLI
ShhShh
Shh
Ptc1Smo Smo
PKB
PDK
PI3K
Scientific rationale: the Hedgehog (Hh) signal transduction pathway
Gli, glioma-associated oncogene homolog zinc finger protein
Cellular proliferation,
differentiation and survival
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ShhShh
ShhShh
Ptc1Smo
Gli1
Sufu
Gli2
Sufu
Gli3
MIM MIM
GLI
ShhShh
GLI
ShhShh
Shh
Ptc1Smo Smo
PKB
PDK
PI3K
Scientific rationale: the Hedgehog (Hh) signal transduction pathway
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)
Pancreatic cancerColon cancerLymphoma
SCLC CML
Pancreatic cancerBreast cancer
BCC
BCCMedulloblasto
ma
Basal Cell Carcinoma (BCC) Hh
activation in 70% of cases
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LDE225 – a potent and selective Smo antagonist
• LDE225 is a novel oral inhibitor of Smo– Structurally distinct from steroidal alkaloids such as
cyclopamine
LDE225
O
N
H
N
N
O
OCF3
Cyclopamine
O
OH
NH
H
H
H
H
H
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LDE225 – preclinical summary
Assay Cell line IC50(nM)
Shh-inducedGli-1 mRNA
Human HEPM 13
Shh-inducedGli-1
LuciferaseMouse TM3 7
5mg/kg
10 mg/kg20 mg/kg
Vehicle
8 10 12 14 16 18 20 220
500
1000
1500
2000
2500
3000
Days post-implantation
Tu
mo
r vo
lum
e (
mm
3)
me
an
± S
EM
Ptch +/-, p53 -/- MB model
LDE225 is a novel oral inhibitor of Smo that potently inhibits Smo-dependent proliferation in vivo in preclinical studies
Gli, glioma-associated oncogene homolog zinc finger protein; Shh, Sonic Hedgehog
Gli-1 mRNA (human)Luciferase (mouse)
Gli-1 promoter
LDE225
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Topical LDE225 (0.75%) in Naevoid Basal Cell Carcinoma Syndrome (Gorlin Syndrome)
• Germ line mutations in Ptch, leading to subsequent development of multiple BCCs
• Established proof of concept• Orphan drug status granted in EU
for BCC in Gorlin Syndrome
Baseline After 4 weeks
Complete responsePartial responseNo response
LDE225 Vehicle
02
46
810
1214
Cum
ulat
ive
num
ber
of tu
mor
s
De Rie MA, et al. Society for Investigative Dermatology (SID) 2010
8 NBCCS patients 27 BCC patientsn=13 LDE225 cream (BID)n=14 Vehicle
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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
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Dose-escalation phaseBayesian logistic regression model using
overdose control
LDE225 Phase I: study designPhase IA, multicenter, open-label, single-agent, dose-escalation study in patients with advanced solid tumors
*Defined as the highest drug dosage not causing DLT in >33% of patients during the first treatment cycle
Decision to dose escalate based on review of toxicities in Cycle 1 and other
clinical, PK, and laboratory data
Declaration of MTD*
MTD expansion phase
Oral, daily LDE225, 28-day cycle
100
mg/
day
200
mg/
day
400
mg/
day
800
mg/
day
1500
mg/
day
Dose levels
Ong
oing
• 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
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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
Primary site of cancer (n)
PancreasLungMedulloblastomaBreastOthers (n≤1)*
01104
00114
31001
43004
20113
953216
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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)
Drug-related AE (n)
GI Toxicity
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 myalgiaMyalgia
2 0
21
00
00
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)AEs with total incidence of ≥2 represented; cut-off date 24 May 2010
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0 24 48 72 96 120 144 168
1
10
100
1000
10000
Time (h)
LD
E2
25 p
lasm
a co
nc.
(n
M)
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
Pharmacokinetic profile after a single dose (7-day run-in)
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)
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PK: relationship between LDE225 dose and plasma exposure (Cmax and AUC) at Day 15
Pla
sma
Cm
ax (n
M)
Pla
sma
AU
C0
-24
(nM
*hr)
1000
2000
3000
4000Cmax Day 15
100 200 400 800 1500
0
Dose (mg/day)
20000
40000
60000
80000AUC0-24 Day 15
0
Target exposure
• Dose-proportional systemic exposure up to 1500 mg/day (R2=0.6019 P=0.0001)
• Two-fold increase in Cmax and five-fold increase in AUC on Day 15 versus Day 1
• Target exposure (AUC) as predicted by preclinical models was achieved by Day 15 at doses ≥400 mg daily
• Variability in exposure was moderate–high (CV%) in AUC (43–104%) and Cmax (38–90%)
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Biomarkers: LDE225-induced changes in skin Gli-1 mRNA expression after 28 days
5
–35
–30
–25
–20
–15
–10
-5
0
100 mg 200 mg 400 mg 800 mg1500 mg
Fo
ld-c
han
ge fr
om b
ase
line
Patients
–1.14 –7.36 –3.17 –3.56 –19.14
12.3% 86.4% 72.0% 94.8%68.4%
Mean Fold Change
Mean % inhibition
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Reduction in Gli-1 expression observed in skin correlated with plasma exposure
Cmax (nM) Day 15 Cmin (nM) Day 15 AUC24 (nM*h) Day 15
PK measurement value
0 1000 2000 3000 0 1000 2000 3000 0 20000 40000 60000
0
–2
–4
Ski
n G
li-1
Red
uctio
n (
Ct)
CT, threshold cycle by RT-PCR analysis
Cohort 1; 100 mg
Cohort 2; 200 mg
Cohort 3; 400 mg
Cohort 4; 800 mg
Cohort 5; 1500 mg
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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
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LDE225 is active in medulloblastomaPatient A (200 mg)
Prior surgery, radiation, 4 chemotherapy regimens and autologous BMT
Partial response following 2 cycles of therapyPatient B (1500 mg)
Prior surgery, radiation, 4 chemotherapy regimens and autologous BMT
Partial metabolic response following 2 cycles of therapy
Baseline C2D28
FDG-PET, fluorodeoxyglucose-positron emission tomography
Pre-treatment Cycle 2 Day 28 MRIA
B
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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
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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