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

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

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

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

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

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

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

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

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

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

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)

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%)

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

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

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 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

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