A phase I dose-escalation study of LDE225, a Smoothened (Smo) antagonist, in patients with advanced ...
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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

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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,3C 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

AAAAA

Ptc1

Ptc1

g

g

GLI

GLI

Shh

Shh

Shh

Shh

Shh

Shh

Shh

Shh

Shh

Smo

Smo

b

b

PI3K

Smo

PDK

PKB

Gli3

Gli1

Gli2

Sufu

Sufu

MIM

MIM

Cellular proliferation, differentiation and survival

CBP/p300

HIP, PDGFR,Gli, Cyclin D1,N-myc, Wnt

mRNAs

Gli1/2

Gli3

Gli, glioma-associated oncogene homolog zinc finger protein


Scientific rationale: the Hedgehog (Hh) signal transduction pathway

Ptc1

Ptc1

g

g

GLI

GLI

Gli3

Gli1

Gli2

Sufu

Sufu

MIM

MIM

Shh

Shh

Shh

Shh

Shh

Shh

Shh

Shh

Shh

Smo

Smo

BCC

b

b

PI3K

BCCMedulloblastoma

Smo

PDK

Pancreatic cancer

Colon cancer

Lymphoma

PKB

Basal Cell Carcinoma (BCC) Hh activation in 70% of cases

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 – a potent and selective Smo antagonist pathway

H

C

F

N

3

O

H

H

O

H

H

H

H

N

N

H

O

O

N

Cyclopamine

O

LDE225

  • LDE225 is a novel oral inhibitor of Smo

    • Structurally distinct from steroidal alkaloids such as cyclopamine


Lde225 preclinical summary
LDE225 – preclinical summary pathway

LDE225

Gli-1 mRNA (human)

Luciferase (mouse)

Gli-1 promoter

Ptch +/-, p53 -/- MB model

3000

Vehicle

2500

5mg/kg

2000

Tumor volume (mm3)

mean ± SEM

1500

1000

10 mg/kg

500

20 mg/kg

0

8

10

12

14

16

18

20

22

Days post-implantation

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


Topical lde225 0 75 in naevoid basal cell carcinoma syndrome gorlin syndrome
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

Complete response

Partial response

No response

14

12

10

8

Cumulative number of tumors

6

4

2

0

LDE225

Vehicle

8 NBCCS patients

27 BCC patients

n=13 LDE225 cream (BID)

n=14 Vehicle

Baseline

After 4 weeks

De Rie MA, et al. Society for Investigative Dermatology (SID) 2010


Phase i study design oral formulation
Phase I study design (oral formulation) Syndrome (

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 Syndrome (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

Oral, daily LDE225, 28-day cycle

Declaration of MTD*

100 mg/day

1500 mg/day

200 mg/day

800 mg/day

400 mg/day

Ongoing

Dose levels

  • 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

Decision to dose escalate based on review of toxicities in Cycle 1 and other clinical, PK, and laboratory data

*Defined as the highest drug dosage not causing DLT in >33% of patients during the first treatment cycle



Most common grade 1 2 aes potentially related to lde225 treatment
Most common grade 1–2 AEs potentially related to LDE225 treatment

AEs with total incidence of ≥2 represented; cut-off date 24 May 2010


Pharmacokinetic profile after a single dose treatment(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

10000

1000

LDE225 plasma conc. (nM)

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

120

144

168

Time (h)


Pk relationship between lde225 dose and plasma exposure c max and auc at day 15
PK: relationship between LDE225 dose and plasma exposure (C treatmentmax and AUC) at Day 15

100

200

400

800

1500

  • 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%)

4000

Cmax Day 15

3000

Plasma Cmax (nM)

2000

1000

0

80000

AUC0-24 Day 15

60000

Plasma AUC0-24 (nM*hr)

40000

Target exposure

20000

0

Dose (mg/day)


Biomarkers lde225 induced changes in skin gli 1 mrna expression after 28 days
Biomarkers: LDE225-induced changes in skin Gli-1 mRNA expression after 28 days

5

0

-5

–10

–15

Fold-change from baseline

100 mg

200 mg

400 mg

800 mg

1500 mg

–20

–25

–30

–35

Patients

–3.56

–7.36

Mean Fold Change

–1.14

–3.17

–19.14

Mean % inhibition

12.3%

68.4%

86.4%

72.0%

94.8%


Reduction in gli 1 expression observed in skin correlated with plasma exposure
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

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

0

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

Skin Gli-1 Reduction (DCt)

.

.

.

.

.

–2

.

.

.

.

.

.

.

–4

0 1000 2000 3000 0 1000 2000 3000 0 20000 40000 60000

PK measurement value

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


Summary of anti tumor activity n 31
Summary of anti-tumor activity (n = 31) with plasma exposure

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
LDE225 is active in medulloblastoma with plasma exposure

Baseline

C2D28

FDG-PET, fluorodeoxyglucose-positron emission tomography

Patient A (200 mg)

Prior surgery, radiation, 4 chemotherapy regimens and autologous BMT

Partial response following 2 cycles of therapy

A

Cycle 2 Day 28

Pre-treatment

MRI

Patient B (1500 mg)

Prior surgery, radiation, 4 chemotherapy regimens and autologous BMT

Partial metabolic response following 2 cycles of therapy

B


Conclusions
Conclusions with plasma exposure

  • 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
Acknowledgements with plasma exposure

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