SK Sandhu1,2, R Wenham3, G Wilding4, M McFadden5, L Sun5, C Toniatti5, M Stroh5, C Carpenter5, J de-Bono1,2, WR Schelman4

First in Human Trial of a Poly(ADP-ribose) Polymerase (PARP) Inhibitor MK-4827 in Advanced

Cancer Patients with Anti-tumor Activity in BRCA-Deficient and Sporadic Ovarian Cancers

1.Drug Development Unit, Royal Marsden NHS Foundation Trust, Sutton, UK 2.The Institute of Cancer Research, Sutton & London, UK

3.H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, US4.University of Wisconsin Carbone Cancer Center, Madison, WI, US

5..Merck & Co., Inc., Whitehouse Station, New Jersey, USA

SSB

PARP

BER

DNA replication fork arrest and collapsePARP

Normal S Phase DNA replication

HR-based repair

Unrepaired SSB

HR-based repair

BRCA1 or BRCA2 deficiency

DNA damageCell death

Normal BRCA1& BRCA2 function

Genomic stability Cell viability

PARP Inhibition and Tumor-Selective Synthetic Lethality

Reliance on error prone DNA repair

Farmer H et al, Nature, 2005;434:917-921Bryant HE et al, Nature, 2005,434:913-917

BRCA1

Germline mutationSomatic mutation

Epigenetic silencing

PTENloss

BER

Stalled replication forksDNA DSB

Cell death

Normal cell or heterozygote

for HR

Germline mutationSomatic mutation

Epigenetic silencingBRCA2

ATM

FAcomplex

FANCD2

RAD51

Cell viability

Tumor-Selective Synthetic Lethality

HR deficient tumor

DNA damage

HRrepair

No HR repair

}

}

OvarianBreast

EndometrialBreastProstateGlioblastoma

Turner N, et al. Nat Rev Cancer.2004;4:814-9Mendes-Pereira AM, et al. EMBO Mol Med. 2009;1:315-22B. Hennessy, et al. J CO 27:15s, 2009 (suppl; abstr 5528)Esteller M, et al.J Natl Cancer Inst.2000;92:564-569

PARPi

Farmer H, et al. Nature, 2005;434:917-921Bryant HE, et al. Nature, 2005;434:913-917McCabe N, et al. Cancer Res. 2006;66:8109-15Press JZ , et al. BMC Cancer 2008;8:1-12

MK-4827

• Highly selective, PARP-1/2 inhibitor

• In vitro monotherapy efficacy:

– BRCA-1 or BRCA-2 deficient• CC50 = 10-90 nM {>10-fold selectivity over BRCA-wt

cells (CC50 ≥ 1500 nM)}– ATM inactivation

• CC50 = 100-300 nM– PTEN deletion

• CC50 = 100-800 nMN

N

C O N H 2

( S )N H

PARP-1 PARP-2 PARP-3 v-PARP TANK-1

3.82.1

1300330570

IC50

Study Objectives

• Primary objectives

– Safety and tolerability, dose limiting toxicities (DLT), maximum tolerated dose (MTD), recommended phase 2 dose (RP2D)

• Secondary objectives

– Pharmacokinetic (PK) and pharmacodynamic (PD) profile

– Preliminary assessment of anti-tumor activity in patients with cancers likely to have a HR DNA repair defects

Methods

• First in human, open-label, Phase I study– Royal Marsden NHS Foundation Trust, Moffitt Cancer Center,

University of Wisconsin Carbone Cancer Center

• Oral once daily dosing; two part study– Dose escalation: Enrichment for BRCA1 and BRCA2 mutation carriers– Dose expansion: Sporadic platinum resistant high grade serous ovarian cancer & castration resistant prostate cancer (CRPC)

Inclusion and Exclusion criteria

• Inclusion criteria– Over the age of 18– Advanced malignancy– Confirmed histological diagnosis – Informed consent– Adequate organ function– ECOG PS of ≤ 2

• Exclusion criteria– Receiving another investigational agent – Hypersensitivity to study drug or analogues– Prior treatment with a PARP inhibitor– Uncontrolled medical condition

300 mg n=9

400 mg n=6

MK4827 Phase I Study: Results

Part A: Dose escalation & MTD confirmation• 59 patients enrolled• Enriched for BRCA1/2 mutation carriers• Safety• PK-PD relationship

Part B: Dose expansion• Safety• PK-PD relationship• Anti-tumor activity in sporadic tumors

* High likelihood of having HR DNA repair defect

MTD cohort

Sporadic platinum resistant high grade serous ovarian cancer*

n=30

Sporadic castration resistant prostate cancer*

n=20

290 mg n=5

210 mg n=6

150 mg n=6

110 mg n=5

80 mg n=6

60 mg n=7

40 mg n=3

30 mg n=6

Patient DemographicsCharacteristics (n=56)

Median Age (Range) 56 (35-74)

Male / Female 12 / 47

ECOG PS 0 / 1 / 2 21 / 36 / 2

Prior systemic treatments

1-2 / ≥3 / ≥4 5 / 14 / 40

Tumor type

Primary Peritoneal / Ovarian

Breast

Prostate (CRPC)

Sarcoma

Melanoma

Colorectal

NSCLC

Other

26

12

5

2

2

4

2

6

Main Adverse Events (All Cycles): Well Tolerated

Main adverse events n=53

Number of total patients (%)

Grade1-2 Grade 3 Grade 4 All Grades

Nausea 24 (45) 1 (2) - 25 (47)

Vomiting 13 (25) 1 (2) - 14 (27)

Diarrhea 10 (19) - - 10(19)

Anorexia 15 (28) - - 15 (28)

Fatigue 18 (34) 2 (4) - 20 (38)

Anemia 9 (17) 3 (6) - 12 (23)

Thrombocytopenia 7 (13) 4 (7) 3 (6) 14 (26)

Neutropenia 7 (13) 1 (2) - 8 (15)

Dose Limiting Toxicities (DLT)

Dose Tumor type DLT Outcome

30 mg Endometrial G3 fatigue Clinical progression

60 mg Breast G3 pneumonitisResolved with use of steroids

and antibiotics

400 mg Ovarian G4 thrombocytopeniaResolved with drug

discontinuation

400 mg Breast G4 thrombocytopeniaResolved with drug

discontinuation

• Thrombocytopenia was dose limiting• MTD = 300mg QD

Preliminary Pharmacokinetic (PK) ProfileCycle1 Day1

Dose, mg

0 100 200 300 400

AU

C 0-2

4, M

*hr

0

10

20

30

40

50

Final Intensive PK

Dose, mg

0 100 200 300 400

AU

C 0-2

4, M

*hr

0

50

100

150

200

Cycle1 Day1

Dose, mg

0 100 200 300 400

Cm

ax,

nM

0

1000

2000

3000

4000

Final Intensive PK

Dose, mg

0 100 200 300 400C

ma

x, n

M0

2000

4000

6000

8000

10000

• Dose proportional pharmacokinetics• Three-fold accumulation in AUC0-24, Cmax and C24 over the 1st cycle• Steady state achieved following one 21-day cycle • Terminal half-life is 37-42 hours

Pharmacodynamic (PD) Profile

• Functional PARP activity in PBMCs: trough levels on C1D21 or C2D1– Percent inhibition calculated using the mean of 2 baseline samples

Dose

%P

AR

P a

ctiv

ity

(rel

ativ

e to

bas

elin

e)

N=18 patients

20

40

60

80

100

120

140

50

30 mg40 mg

80 mg110 mg

150 mg210 mg

290 mg400 mg

60mg

Gamma H2AX Foci Induction in Tumor Biopsy

Cycle 1 day 22MK4827 300mg

•Paired fresh frozen tumor biopsy in a BRCA2 mutation carrier with breast cancer•Stained for gamma H2AX foci pre and post treatment

Nuclear staining

γH2AX foci

Cycle 1 day1, predoseMK4827 300mg

MK-4827 Anti-Tumor Efficacy

Patients on 400mg were dose reduced to 300mg in C2

Ongoing treatment

■

Stable disease for ≥ 120 days

Partial response by RECIST criteria

GCIG CA125 partial response

BRCA1 or BRCA2 mutation carrier+

0 50 100 150 200 250 300 350 400

NSCLC■Ovarian

Ovarian■NCSLC

Ovarian■Ovarian■Ovarian■Ovarian■Breast■Breast

■Ovarian■Ovarian■Ovarian

Tumo

r Typ

e

Days on Study

290 mg

210mg

150mg

110mg

110mg

80mg

60mg

40mg

60mg

60mg

110mg

400mg+

++

+

+

++

+ 300mg

+

Increasing dose

Increasing dose

Tumor type Number of evaluable patients

Dose

(mg)

Number of BRCA1 & 2 mutation carriers in the cohort

RECIST partial response

RECIST

stable disease

for 60 days

RECIST

stable disease

for 120 days

Clinical

benefit rate

(PR &SD

≥ 120 days)

Ovarian / primary peritoneal cancer

19 60

80

110

150

210

290

300

400

2

2

3

3

1

3

2

3

-

1

2

-

-

1

1

1

-

-

-

-

1

-

1

2

1

-

-

-

-

-

-

-

37%

Breast

cancer

4 150

210

300

1

2

1

1

1

-

-

1

-

-

-

-

50%

Hereditary Ovarian and Breast Cancer: Preliminary Response Data

Hereditary Breast and Ovarian Cancer

Baseline

Day 98Baseline

Day 61Baseline

Baseline

BRCA1 mutation carrier

BRCA2 mutation carrierBRCA2 mutation carrier

Baseline Day 46

24.5mm14mm

71mm30mm

Hereditary Ovarian Cancer: CA125 Response

BRCA1 Mutation Carrier

0

100

200

300

400

500

600

700

05/0

1/20

10

12/0

1/20

10

19/0

1/20

10

26/0

1/20

10

02/0

2/20

10

09/0

2/20

10

16/0

2/20

10

23/0

2/20

10

02/0

3/20

10

09/0

3/20

10

16/0

3/20

10

23/0

3/20

10

30/0

3/20

10

06/0

4/20

10

13/0

4/20

10

20/0

4/20

10

27/0

4/20

10

04/0

5/20

10

Sample Date

CA12

5 U/

ml GCIG CA125 response

95% reduction

MK-4827 290mg

Sporadic Ovarian Cancer Patient

• FIGO Stage 3B high grade serous ovarian cancer; No family history*• Five prior lines of platinum-based chemotherapy; last platinum free

interval of 7 months• 357 days on MK4827, ongoing PR by RECIST & GCIG CA125 criteria

Baseline Day 101

* Studies of HR DNA repair proficiency ongoing

Sporadic Ovarian Cancer: Ca125 Response

MK-4827 increased from 60mg to 210mg

Maintained PR by RECIST criteria

0

200

400

600

800

1000

1200

1400

18/0

5/20

09

01/0

6/20

09

15/0

6/20

09

29/0

6/20

09

13/0

7/20

09

27/0

7/20

09

10/0

8/20

09

24/0

8/20

09

07/0

9/20

09

21/0

9/20

09

05/1

0/20

09

19/1

0/20

09

02/1

1/20

09

16/1

1/20

09

30/1

1/20

09

14/1

2/20

09

28/1

2/20

09

11/0

1/20

10

25/0

1/20

10

08/0

2/20

10

22/0

2/20

10

08/0

3/20

10

22/0

3/20

10

05/0

4/20

10

19/0

4/20

10

Sample Date

CA

125

U/m

l GCIG CA125 response

94% reduction

MK-4827 60mg

Conclusions

• Safety

– MK-4827 was well tolerated

– Continuous oral administration at 300mg is the MTD

• PK

– Dose proportional pharmacokinetic profile

• PD

– Proof of mechanism has confirmed PARP inhibition

from doses of ≥ 80mg

• Compelling anti-tumor activity observed

– Heavily pre-treated BRCA1 and BRCA2 mutation carriers

– Preliminary anti-tumor activity seen in sporadic cancers

Acknowledgements

• Patients and their families

• DDU, Royal Marsden Hospital– Stan Kaye– Richard Baird– Martin Forster– Elizabeth Sheridan– Jen Lewis– Alima Rahman

• The Institute of Cancer Research– Alan Ashworth– Chris Lord

• H. Lee Moffitt Cancer Center & Research Institute– Irene Williams-Elson

• University of Wisconsin Carbone Cancer Center– Jennifer Heideman

• Merck & Co. Inc – Judith Allen

• ASCO Cancer Foundation