m. j. pishvaian*, r. slack*, a. witkiewicz +, a. r. he*, j. j. hwang*, a. hankin*, k. dorsch-vogel*,...
TRANSCRIPT
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
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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