M. J. Pishvaian*, R. Slack*, A. Witkiewicz+, A. R. He*,

J. J. Hwang*, A. Hankin*, K. Dorsch-Vogel*, D. Kuda*, T. McAndrew*, L. M. Weiner*, J. Marshall*, J. R. Brody+

A Phase II study of ABT-888 + temozolomidein patients with heavily pretreated,

metastatic colorectal cancer

*Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC +Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA

Financial Disclosures

• This clinical trial is funded by the

Otto J. Ruesch Center for the Cure of GI Cancers, Lombardi Comprehensive Cancer Center.

• Abbott Inc. has provided research funding for a portion of the correlative science

• I have no personal financial disclosures

Georgetown Lombardi

XRCC1

LigIII

PNK 1

pol β

PARP

Mechanisms of DNA Repair: PARP (Poly(ADP-ribose) polymerase)

DNA DAMAGE Environmental factors

(UV, radiation, chemicals)Normal physiology

(DNA replication, ROS)

Chemotherapy

(e.g. alkylating agents)

Radiotherapy

Tutt, A, et al, JCO 27:18s, 2009 (suppl; abstr CRA501) Helleday T, et al. Nat Rev Cancer. 2008;8:193-204

Inhibition of PARP• Prevents recruitment of DNA repair enzymes• Leads to failure of single strand break repair

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PARP• Critical DNA repair enzyme (SSB, BER)• Often overexpressed in cancer cells• Confers resistance to chemotherapy and

radiation

Unrepaired break site replication fork arrest• Leads to degeneration into double-strand breaks• Ultimately chromosomal catastrophe cell death

Cell Death

Background

• ABT-888• Oral PARP-1, 2 inhibitor

• Proven PARP inhibition in vitro, and in vivo

• Potentiates activity of multiple chemotherapies in

pre-clinical models including temozolomide

• Temozolomide (TMZ)• Oral potent atypical alkylating agent

• Ongoing trials in combination with ABT-888

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Donawho, CK, et al, Clin Cancer Res 2007;13(9) May1, 2007Palma, JP, et al, Clin Cancer Res 2009;15(23):7277–90Kummar, S, et al, JCO. 2009 Jun 1;27(16):2705-11Delaney, CA, et al, Clin Cancer Res, 6: 2860-2867, 2000Raymond, E, et al, Clin Cancer Res, 3: 1769-1774, 1997.

PARP is a Promising Target in CRC

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• Overexpression of PARP in CRC

leads to chemotherapy resistance

• ABT-888 + temozolomide cell death

• Many CRCs may be exquisitely sensitive to PARP inhibitor-based therapy

• 5-7% with mismatch repair gene defects (dMMR)

• Up to 40% PTEN deficient

(defect in homologous recombination)

Loupakis F, et al, JCO 27:2622-9, 2009McCabe N, et al, Can Res 66:8109-15, 2006

Liu, X., et al, Mol Cancer Res, 7: 1686-1692, 2009Horton, TM, et al, Mol Cancer Ther, 8: 2232-2242, 2009

DMSO

TMZ

ABT-888

TMZ + ABT-888

SW480 HCT116

0

25000

50000

75000

100000 ***

Ce

ll N

um

be

r

***

TMZ + ABT-888

• Inclusion Criteria

• Exclusion Criteria

• Untreated CNS metastases

• Active severe infection

• Active cardiovascular disease

• Women who were pregnant or breastfeeding

• Anticipated patient survival under 3 months

Inclusion/Exclusion Criteria

• Metastatic CRC• Measurable or evaluable

disease• Adequate hepatic, bone

marrow, and renal function • Age ≥ 18 years• ECOG performance status 0-2

• Progression on or ineligible for all standard therapies:

• Fluoropyrimidine• Oxaliplatin• Irinotecan• Bevacizumab• Cetuximab/Panitumumab

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Trial Design- Single Arm, Phase II

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Restaging studiesevery 8 weeks

Weeks on study

AT

AT

12 161 2 3 4 5 6 7 80

ABT-888

TMZ

ABT-888

TMZ

Days of the week

ABT-888 - 40 mg BID

TMZ - 150mg/m2 QD

1 2 3 4 5 6 7 III II III III III III II

4 week cycles 4 week cycles

Trial Design

• Primary endpoint - Disease control rate (DCR)• Complete response, partial response, or stable disease (after two cycles)

• Secondary endpoints• Objective response rate, progression free survival, overall survival

• Correlation between DCR and MMR and PTEN expression

• Simon’s two stage optimal design• P0 = 10%, P1 = 25%, =10%, =10% (Power = 90%)

• Stage I = 21 patients (3/21 = 14% respond, then proceed to Stage II)

• Stage II = 29 additional patients (50 total)

• If DCR ≥ 8/50 = 16% Further study justified

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Results - Patients

• 09/09 to 06/11, 49 patients enrolled• 51% KRAS mutant

• Median Age – 55 years• Range 36 to 72

• 29 Male, 21 Female• Median ECOG PS – 1

• 0 n=15

• 1 n=32

• 2 n=2

• Median number of prior

chemotherapy regimens - 3.5 • Range 2 to 7

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0

10

20

30

40

50

60

70

80

90

100

Fluoro

pyrim

idine

Oxalip

latin

Irino

teca

n

Bevac

izum

ab

Cetux

/Pan

itum

umab

Other

Percent ofPatients

Prior Therapies

Adverse Events

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• Only 1 patient withdrew due to toxicity - pancytopenia

1,2 3,4

Toxicity N (%) N (%)

Thrombocytopenia 20 (41) 4 (8)

Anemia 17 (35) 1 (2)

Leucopenia 3 (6) 1 (2)

Nausea 24 (49) 0 (0)

Fatigue 16 (33) 0 (0)

Vomiting 7 (14) 0 (0)

Anorexia 5 (10) 0(0)

GradeN=49

Evidence of Anti-Cancer Activity

• Disease Control• 11 (2 confirmed PRs)

• DCR = 22%

• Median Duration of Disease Control

• 22 weeks

• Range 15 – 40 weeks

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• As of 06-01-2011 - ITT analysis of 49 patients

• Median overall survival• 6.3 months

0 5 15 2010

Months

0

20

40

60

80

100

Percent Surviving

Duration of Disease Control

Individual Patients

Wee

ks = Progression (78%)

= Disease Control (22%)= Partial Response (4%)

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Evidence of Anti-Cancer Activity

Patient 26 – 69 year old female

34% reduction

34 wks on study

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April, 2010

August, 2010

• Good Tissue Acquisition• 45/49 archived surgical specimens evaluable• 7/9 fresh serial tumor evaluable

• Pre-treatment and Day 8

• Fixed AND frozen samples

• Mismatch repair protein expression• Increased DCR in dMMR tumors

• PTEN expression• Increased DCR in PTEN-deficient tumors

Correlative Studies

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Correlative Studies - MMR

• Assessed MMR status by IHC on paraffin samples• MLH-1, MSH-2, PMS-2, and MSH-6

• 35 of 49 samples assessed to date• No MMR defects detected in any of the patients• Can not assess for any association between MMR status and DCR

Georgetown LombardiLindor, et al, JCO, 20: 1043-1048, 2002.

Wright, CL, et al, Am J Surg Pathol 2003;27:1393–1406

Correlative Studies - PTEN

• Assessed PTEN protein expression by IHC• To date, no clear relationship between expression and DCR

N=5N=13

Normal

Cancer

Cancer

PTEN Positive CRC

PTEN Negative CRC

Loupakis, F, et al, JCO 2009, 27:2622-2629Georgetown Lombardi

H-score = (%1+cellsX1) + (%2+cellsX2) + (%3+cellsX3)

PTEN

Correlative Studies

No Apparent Correlation

Pre-clinically Supported

Markers ?

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Patient Tumor Samples

MGMT Methylation

dMMR PatientsNeeded

MMR?

DNA Repair SNPs Serum microRNA

Investigational Markers

DNA Repair Expression Panel

Results Pending

?

Correlative Studies - DNA Repair Expression Panel

• RNA from tumor samples• Mini-DNA array

• 90 DNA repair genes

• Pre-treatment vs. Day 8

• Expand analysis• Predictive markers

• Responsive signature

• Resistance markers

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Conclusions

• ABT-888 plus TMZ is a well tolerated oral combination

• There is evidence of anti-cancer activity in refractory colon cancer patients:• Partial response• Prolonged stable disease

• Anti-cancer activity even in MMR-proficient patients

• Correlative studies for predictive subgroups are pending• Good tissue acquisition rate

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Study Expansion

• Evaluate efficacy in MMR-deficient subgroup• Identify predictive markers of response• Aim to initiate phase II trial in selected subgroups

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Primary Cohort (50 Patients)

Enrollment completed

20 Patient – dMMR Cohort

20 Patient – High dose TMZ Cohort

Increased TMZ doseGreater DNA damage

Mandatory “Fresh” pre-tx biopsies

Pre-clinically selectedPredictive marker

Acknowledgments

• Biostatistician• Rebecca Slack, MS

• Clinical Care and CRMO• John Marshall, MD• Louis M. Weiner, MD• Jimmy Hwang, MD• A. Ruth He, MD, PhD• Amy Hankin, PA• Karen Vogel, RN• Divyesh Kukadiya, BS• Marion Hartley, PhD

• Thomas Jefferson• Jonathan Brody, PhD• Agnieszka Witkiewicz, MD

• Indivumed• Nina Gabelia, MD, MPH

• Lombardi Research• Anton Wellstein, MD, PhD• Narayan Shivapurkar, PhD• Histopathology and Tissue

Shared Resource

• Abbott• Meeta Jaiswal, PhD

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• Otto J. Ruesch Center for the Cure of GI Cancer• The patients and their families