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A Phase II study of ABT-888 + temozolomide in patients with heavily pretreated, metastatic colorectal cancer. 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 +.

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slide1

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

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+

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

financial disclosures
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

mechanisms of dna repair parp poly adp ribose polymerase
Mechanisms of DNA Repair: PARP (Poly(ADP-ribose) polymerase)

Environmental factors

(UV, radiation, chemicals)

Chemotherapy

(e.g. alkylating agents)

Normal physiology

(DNA replication, ROS)

Radiotherapy

PNK 1

XRCC1

pol β

LigIII

PARP

DNA DAMAGE

  • PARP
  • Critical DNA repair enzyme (SSB, BER)
  • Often overexpressed in cancer cells
  • Confers resistance to chemotherapy and radiation
  • Inhibition of PARP
  • Prevents recruitment of DNA repair enzymes
  • Leads to failure of single strand break repair
  • Unrepaired break site  replication fork arrest
  • Leads to degeneration into double-strand breaks
  • Ultimately  chromosomal catastrophe cell death

Cell Death

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Tutt, A, et al, JCO 27:18s, 2009 (suppl; abstr CRA501)

Helleday T, et al. Nat Rev Cancer. 2008;8:193-204

background
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

Donawho, CK, et al, Clin Cancer Res 2007;13(9) May1, 2007

Palma, JP, et al, Clin Cancer Res 2009;15(23):7277–90

Kummar, S, et al, JCO. 2009 Jun 1;27(16):2705-11

Delaney, CA, et al, Clin Cancer Res, 6: 2860-2867, 2000

Raymond, E, et al, Clin Cancer Res, 3: 1769-1774, 1997.

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parp is a promising target in crc
PARP is a Promising Target in CRC

DMSO

TMZ

ABT-888

TMZ + ABT-888

TMZ

+ ABT-888

  • 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)

100000

***

75000

50000

Cell Number

***

25000

0

SW480

HCT116

Loupakis F, et al, JCO 27:2622-9, 2009

McCabe N, et al, Can Res 66:8109-15, 2006

Liu, X., et al, Mol Cancer Res, 7: 1686-1692, 2009

Horton, TM, et al, Mol Cancer Ther, 8: 2232-2242, 2009

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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

Inclusion/Exclusion Criteria
  • 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

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trial design single arm phase ii
Trial Design- Single Arm, Phase II

8

1

2

3

4

5

6

7

0

1 2 3 4 5 6 7

III

III

III

III

III

II

II

TMZ - 150mg/m2 QD

ABT-888 - 40 mg BID

4 week cycles

4 week cycles

ABT-888

ABT-888

A

T

A

T

TMZ

TMZ

16

12

Weeks on study

Restaging studies

every 8 weeks

Days of the week

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trial design
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%, a=10%, b=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
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

Prior Therapies

100

90

80

70

60

Percent of

Patients

50

40

30

20

10

0

Other

Irinotecan

Oxaliplatin

Bevacizumab

Fluoropyrimidine

Cetux/Panitumumab

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adverse events
Adverse Events
  • Only 1 patient withdrew due to toxicity - pancytopenia

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evidence of anti cancer activity
Evidence of Anti-Cancer Activity

100

80

60

Percent

Surviving

40

20

0

0

5

10

15

20

Months

  • As of 06-01-2011 - ITT analysis of 49 patients
  • Disease Control
    • 11 (2 confirmed PRs)
    • DCR = 22%
  • Median Duration of Disease Control
    • 22 weeks
    • Range 15 – 40 weeks
  • Median overall survival
    • 6.3 months

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slide12

Evidence of Anti-Cancer Activity

40

Duration of Disease Control

30

= Disease Control (22%)

= Partial Response (4%)

= Progression (78%)

Weeks

20

10

0

Individual Patients

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patient 26 69 year old female
Patient 26 – 69 year old female

April, 2010

34% reduction

34 wks on study

August, 2010

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correlative studies
Correlative Studies
  • 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

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correlative studies mmr
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

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Lindor, et al, JCO, 20: 1043-1048, 2002.

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

correlative studies pten

Cancer

Normal

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

PTEN Positive CRC

N=13

N=5

Cancer

PTENNegative CRC

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

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

correlative studies1
Correlative Studies

PTEN

MMR

MGMT

Methylation

Investigational

Markers

DNA Repair SNPs

Serum microRNA

DNA Repair

Expression Panel

?

Pre-clinically

Supported

Markers

No Apparent Correlation

?

?

dMMR Patients

Needed

Results

Pending

Patient Tumor

Samples

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correlative studies dna repair expression panel
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
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
Study Expansion

20 Patient – dMMR Cohort

Pre-clinically selected

Predictive marker

Primary Cohort (50 Patients)

Enrollment completed

20 Patient – High dose TMZ Cohort

Increased TMZ dose

Greater DNA damage

Mandatory “Fresh” pre-tx biopsies

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

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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

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

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