First-in-Man Phase Ι Safety, Pharmacokinetic and Pharmacodynamic

Analysis of the Oral MEK-Inhibitor AS703026 (2 Regimens) in Patients With

Advanced Solid Tumors   

J.P. Delord, N. Houédé, A. Awada, A. Taamma, S.J. Faivre, T. Besse-Hammer, A. Italiano, C. Vignaud,

M. Donica, E. Raymond

Institut Claudius Regaud, Toulouse, France,Institut Bergonié, Bordeaux, France,

Institut Jules Bordet, Brussels, Belgium,Merck Serono SA, Geneva, Switzerland,

Hôpital Beaujon, Clichy, France.

• A biaryl amine derivative

• In vitro and in vivo pharmacology:– High selectivity for MEK1/2– Anti-proliferative effects in tumor cell lines– Efficacy in xenograft models with activated MAPK signaling

MEK Inhibitor AS703026

•HCl

MW: 467.8 KDa (HCl salt)

AS703026 Phase Ι Trial Objectives

• Primary objective– To determine the MTD for 2 distinct dosing schedules

administered orally once daily

• Secondary objectives– To provide preliminary findings on the safety profile

– To assess the pharmacokinetics

– To assess biological activity and pharmacodynamic markers in blood and in pre/post dosing tumor biopsies in a subset of patients

– To assess the antitumor activity in patients with solid tumors

AS703026 Phase Ι Trial Design

• 3 + 3 Open-label Phase I trial• Two dosing schedules tested

• AS703026 orally once daily (after at least 2 hours fasting)• Dose escalation: separate for each schedule

– If no grade 2 toxicity observed a 100% dose increment

– If a grade 2 toxicity is observed: Modified Fibonacci

Schedule 1

Day 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 1

Schedule 2

AS703026 Phase Ι Trial Baseline Patient Characteristics

Schedule 1n=43

Schedule 2n=42

Gender Male 25 27

Female 18 15

Age Median 59 61.5

Ranges 34-75 35-77

Performance Status 0 26 21

1 17 21

Previous systemic treatment

1 line 2 2

2 lines 41 40

Other: breast, esophagus, gall bladder, head & neck, lung, mesothelioma, ovary, pancreas, renal, sarcoma, thyroid, bladder

AS703026 Phase Ι Trial - Dose EscalationSchedule 1: dosing days 1-5, 8-12, 15-19 q 3 weeks Schedule 2: dosing days 1-15 q 3 weeks

Dose level AS703026 (mg/day) n AS703026 (mg/day) n

1 1 5 1 3

2 1.5 3 2 3

3 2.5 3 3.5 3

4 3.5 3 5 3

5 7 3 7 3

6 14 3 14 5

7 28 6* 28 3

8 45 3 45 3

9 68 4 68 3

10 94 3 94 3

11 120 7** 120 4

12 150 3

13 195 3

Total 43 42

Cohort expanded due to occurrence of DLT: * LFT elevation, **retinal vein occlusion

AS703026 Phase Ι TrialTreatment Exposure

Number of initiated cycles per patient

1 mg/day

1.5 mg/day

2.5 mg/day

3.5 mg/day

7 mg/day

14 mg/day

28 mg/day

45 mg/day

68 mg/day

94 mg/day

120 mg/day

Schedule 1Dose level

Number of initiated cycles

0 1 2 3 4 5 6 7 8 9 10 11

150 mg/day

195 mg/day

Schedule 2

Number of initiated cycles

0 1 2 3 4 5 6 7 8 9 10 11

2.0 mg/day

5.0 mg/day

**

*

*

** *

*patient ongoing

AS703026 Phase Ι TrialMost Common Adverse Events (≥15% of patients in at least one schedule)

All AEs are grade 1-2

AS703026 Phase Ι TrialDose Limiting Toxicity

• Schedule 1: – DL 7 (28 mg/day):

• 1 / 6 patients: Grade 3 Liver function test elevation (treatment delay more than 2 weeks)

– DL 11 (120 mg/day): • 1 / 3 patients: Grade 2 Retinal Vein Occlusion (cycle 3)• Cohort expansion ongoing

• Schedule 2:– No DLT up to 195 mg/day– Dose escalation ongoing

AS703026 Phase Ι TrialFocus on Ocular Adverse Events

• Most common adverse events were: – abnormal perception of colors

– blurred vision

– visual field defect

• Most reported adverse events were mild to moderate (CTCAE grade 1-2)

• Ocular adverse events often occurred early after first dosing (median: 3 days [range 1-105])

• Visual disturbances usually resolved spontaneously while remaining on treatment

AS703026 Phase Ι Trial PK Evaluation – Preliminary Results

• Indication for dose-proportional increase in Cmax and AUC

• Median Tmax is 1 hour (range 0.5 – 4.0 h)

• Median terminal elimination half-life (t1/2) is 5.1 hours

• Exposure at 120 mg Day 1 (n=7):

• Median Cmax 670 ng/mL

• Median AUC 2270 ng*h/mL

Mean Cmax – by dose , Day 1 (n=80)

0

200

400

600

800

1000

1200

0 10 20 30 40 50 60 70 80 90 100 110 120

Dose (mg)M

ea

n C

ma

x (n

g/m

L)

0

20

40

60

80

100

120

140

160

1 1.5 2.5 3.5 7 14 28 45 68 94 120

AS703026 Phase Ι Trialp-ERK Inhibition in PBMC – Preliminary Results

Percentage of pERK inhibition compared with baseline

across dose levels (Cycle 1 Day 1)

• Sustained inhibition of pERK• Dose dependent inhibition of pERK at 2

hrs post administration leading to ≥ 80% inhibition at 28 mg and above

Dose (mg)

0

20

40

60

80

100

120

140

160

perc

ent_

var

Pre-dose 2h 8h 24h

Chart

% o

f p

ER

K v

s b

ase

line

Time course of % of pERK inhibition compared with baseline

Pt 3186 (120mg)

Time point

% o

f p

ER

K v

s b

ase

line

AS703026 Phase Ι TrialAnti-Tumor Activity – Schedules 1 & 2

28 68

68 12068

94 4528 28 28 28

4594 68 45 120 45 28 120 94 120 28 94 68 94 195

Maximum reduction from baseline in tumor size per individual patient

Both schedules (DL ≥28 mg/day)

% t

um

or

cha

ng

e f

rom

ba

selin

e [

sum

of

targ

et

lesi

on

s]

-80

-70

-60

-50

-40

-30

-20

-10

0

10

20

30

40

50

60

70

80

90

100

MelanomaCRCOther

Patient receiving Schedule 1; Patient receiving Schedule 2No. of treated patients = 46No. of treated patients with measurable disease at baseline and ≥ one tumor assessment on-study = 26

AS703026 Phase Ι Trial

Baseline: 03 July 2009 End of Cycle 1: 21 July 2009

Patient 2960. Male, 70 years, right inguinal melanoma in 2007 with metachronous lung metastasis that progressed after IFN, dacarbazine and fotemustine

AS703026: 68 mg/day

AS703026 Phase Ι TrialSummary

• AS703026 is a highly selective oral small molecule that inhibits MEK1/2 phosphorylation

• AS703026 has been tested in this phase I trial in solid tumor patients using two dosing schedules

• In the 5-day on / 2-day off schedule, one DLT retinal vein occlusion occurred at 120 mg/day, cycle 3. Cohort expansion is ongoing

• In the 2-week on / 1-week off schedule, dose escalation is ongoing

AS703026 Phase Ι TrialConclusions

• Adverse events are usually mild to moderate and reversible during treatment or after dose interruption

• Pharmacokinetic parameters seem to be dose-proportional across the dose range investigated

• Almost complete and sustained (>8h) pERK inhibition is observed in PBMC at AS703026 doses ≥ 28 mg/day

• Three partial responses have been reported in melanoma

Acknowledgements

• Hôpital Beaujon, Clichy, France– Pr Eric Raymond– Pr Sandrine Faivre– Fateh Cheklat

• Institut Claudius Regaud, Toulouse, France– Pr Jean-Pierre Delord– Dr Yann Bergé – Muriel Laumond

• Institut Bergonié, Bordeaux, France– Dr Nadine Houédé– Dr Antoine Italiano– Alejandro Gobema

• Institut Jules Bordet, Brussels, Belgium– Dr Ahmed Awada– Dr Tatiana Besse-Hammer– Michel Dubuisson

• Merck Serono– Sabrina Bigeard– Franck Brichory– Jerome Chague– Ann Clark– Patricia Digon– Athos Gianella-Borradori– Christian Lüpfert– Marco Minerdo– Giacomo Mordenti– Janet Ogden– Stefano Ongarello