First in Human Trial of a Poly(ADP-
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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. SK Sandhu 1,2 , R Wenham 3 , G Wilding 4 , M McFadden 5 , L Sun 5 ,

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Sk sandhu 1 2 r wenham 3 g wilding 4 m mcfadden 5 l sun 5

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

SK Sandhu1,2, R Wenham3, G Wilding4, M McFadden5, L Sun5,

C Toniatti5, M Stroh5, C Carpenter5, J de-Bono1,2, WR Schelman4

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, US

4.University of Wisconsin Carbone Cancer Center, Madison, WI, US

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


Parp inhibition and tumor selective synthetic lethality

PARP Inhibition and Tumor-Selective Synthetic Lethality

Normal S Phase DNA replication

SSB

BER

PARP

DNA replication fork arrest and collapse

PARP

Unrepaired SSB

Normal BRCA1& BRCA2 function

BRCA1 or BRCA2 deficiency

HR-based repair

HR-based repair

Reliance on error prone DNA repair

Genomic stability

Cell viability

DNA damage

Cell death

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

Bryant HE et al, Nature, 2005,434:913-917


Sk sandhu 1 2 r wenham 3 g wilding 4 m mcfadden 5 l sun 5

Tumor-Selective Synthetic Lethality

DNA damage

}

Germline mutation

Somatic mutation

Epigenetic silencing

BER

PARPi

BRCA1

Ovarian

Breast

Germline mutation

Somatic mutation

Epigenetic silencing

Stalled replication forks

DNA DSB

BRCA2

ATM

Normal cell

or heterozygote

for HR

HR deficient

tumor

FANCD2

FA

complex

HR

repair

No HR

repair

RAD51

Endometrial

Breast

Prostate

Glioblastoma

PTEN

loss

}

Cell viability

Cell death

Turner N, et al. Nat Rev Cancer.2004;4:814-9

Mendes-Pereira AM, et al. EMBO Mol Med. 2009;1:315-22

B. Hennessy, et al. J CO 27:15s, 2009 (suppl; abstr 5528)

Esteller M, et al.J Natl Cancer Inst.2000;92:564-569

Farmer H, et al. Nature, 2005;434:917-921

Bryant HE, et al. Nature, 2005;434:913-917

McCabe N, et al. Cancer Res. 2006;66:8109-15

Press JZ , et al. BMC Cancer 2008;8:1-12


Mk 4827

PARP-1

PARP-2

PARP-3

v-PARP

TANK-1

3.8

2.1

1300

330

570

IC50

C

O

N

H

2

N

H

N

(

S

)

N

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 nM


Study objectives

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

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 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


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

MK4827 Phase I Study: Results

400 mg n=6

300 mg n=9

MTD cohort

290 mg n=5

Sporadic platinum resistant

high grade serous ovarian cancer*

n=30

210 mg n=6

150 mg n=6

110 mg n=5

Sporadic castration resistant prostate cancer*

n=20

80 mg n=6

60 mg n=7

40 mg n=3

30 mg n=6

* High likelihood of having HR DNA repair defect


Sk sandhu 1 2 r wenham 3 g wilding 4 m mcfadden 5 l sun 5

Patient Demographics


Main adverse events all cycles well tolerated

Main Adverse Events (All Cycles): Well Tolerated


Dose limiting toxicities dlt

Dose Limiting Toxicities (DLT)

  • Thrombocytopenia was dose limiting

  • MTD = 300mg QD


Preliminary pharmacokinetic pk profile

Preliminary Pharmacokinetic (PK) Profile

  • 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

Pharmacodynamic (PD) Profile

140

120

100

80

%PARP activity (relative to baseline)

60

50

40

20

60mg

40 mg

80 mg

30 mg

150 mg

210 mg

290 mg

400 mg

110 mg

N=18 patients

Dose

  • Functional PARP activity in PBMCs: trough levels on C1D21 or C2D1

    • Percent inhibition calculated using the mean of 2 baseline samples


Gamma h2ax foci induction in tumor biopsy

Nuclear staining

γH2AX foci

Gamma H2AX Foci Induction in Tumor Biopsy

Cycle 1 day 22

MK4827 300mg

Cycle 1 day1, predose

MK4827 300mg

  • Paired fresh frozen tumor biopsy in a BRCA2 mutation carrier with breast cancer

  • Stained for gamma H2AX foci pre and post treatment


Mk 4827 anti tumor efficacy

+

400mg

+

Increasing

dose

300mg

+

290 mg

+

210mg

+

150mg

110mg

+

110mg

+

80mg

+

60mg

110mg

+

Increasing

dose

60mg

60mg

40mg

Stable disease for ≥ 120 days

Partial response by RECIST criteria

GCIG CA125 partial response

+

Ongoing treatment

BRCA1 or BRCA2 mutation carrier

MK-4827 Anti-Tumor Efficacy

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


Sk sandhu 1 2 r wenham 3 g wilding 4 m mcfadden 5 l sun 5

Hereditary Ovarian and Breast Cancer: Preliminary Response Data


Sk sandhu 1 2 r wenham 3 g wilding 4 m mcfadden 5 l sun 5

Day61

Baseline

14mm

24.5mm

Hereditary Breast and Ovarian Cancer

Baseline

BRCA1 mutation carrier

Baseline

Day46

Baseline

Baseline

Day98

71mm

30mm

BRCA2 mutation carrier

BRCA2 mutation carrier


Hereditary ovarian cancer ca125 response

Hereditary Ovarian Cancer: CA125 Response

GCIG CA125 response

95% reduction

MK-4827 290mg


Sporadic ovarian cancer patient

Sporadic Ovarian Cancer Patient

Baseline

Day 101

  • 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

* Studies of HR DNA repair proficiency ongoing


Sporadic ovarian cancer ca125 response

Sporadic Ovarian Cancer: Ca125 Response

GCIG CA125 response

94% reduction

Maintained PR by RECIST criteria

MK-4827 60mg

MK-4827 increased

from 60mg to 210mg


Conclusions

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

Acknowledgements


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