A Phase I/II Study of ABT-888, 5-fluorouracil
and oxaliplatin in patients with metastatic
pancreatic cancer
M. J. Pishvaian*, H. Wang*, T. Zhuang*, A. R. He*,
J. J. Hwang*, A. Hankin*, L. Ley*, K. White*, S. Littman+,
L. M. Weiner*, J. L. Marshall*, J. R. Brody+
*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 related to
this work
Pishvaian, et al
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Metastatic Pancreatic Cancer
• Survival rates are poor
• FOLFIRINOX
• Gemcitabine + Abraxane
• But OS still <1 year
• Novel Targets
• DNA damage control?
Is there a therapeutic
opportunity here?
Pishvaian, et al
Conroy, et al, NEJM, 2011
Von Hoff, JCO, 2011
Jones, et al, Science. 2008
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Mechanisms of DNA Repair:
PARP (Poly(ADP-ribose) polymerase)
DNA DAMAGE
PNK 1
XRCC1
pol β
LigIII
Chemotherapy
Environmental factors
(e.g. alkylating agents) (UV, radiation, chemicals)
Normal physiology
Radiotherapy
(DNA replication, ROS)
PARP
• Critical DNA repair enzyme (SSB, BER)
• Often overexpressed in cancer cells
• Confers resistance to chemotherapy and radiation
PARP
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
Pishvaian, et al
Tutt, A, et al, JCO /ASCO, 2009
Helleday T, et al. Nat Rev Cancer, 2008
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• ABT-888
•
•
•
Oral PARP-1, 2 inhibitor
Proven PARP inhibition in vitro/in vivo
Potentiates activity of multiple
chemotherapies in
pre-clinical models
• Addition of the PARP inhibitor ABT-888
 increased sensitivity to cisplatin
Emty Vector
PARP.R355D(Mut)
PARP.E988A(Mut)
PARP.W318R(Mut)
1.0
100
50
0.5
0.0
0
0
20
30
40
Cisplatin alone
ABT-888+ Cisplatin
1.0
100
50
0.5
0.0
0
0
Pishvaian, et al
10
M Oxaliplatin
% surviving cells
• Exogenous mutant PARP
 increased sensitivity to oxaliplatin
% surviving cells
PARP Inhibition Increases Pancreatic
Cancer Cell Sensitivity to Chemotherapy
Brody, et al, unpublished data
Donawho, CK, et al, Clin Cancer Res 2007
Palma, JP, et al, Clin Cancer Res 2009
Kummar, S, et al, JCO. 2009
2
4
6
M Cisplatin
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Homologous Recombination Deficient Cells
Are More Susceptible to PARP Inhibition
• Homologous recombination enzymes are critical for DNA repair
•
Defects in BRCA-1, -2, PALB-B2, FANC  increased sensitivity to
DNA-damaging chemotherapy and to PARP inhibition
• BRCA-2 mutations in pancreatic cancer
•
5 – 17% of pancreatic cancer patients carry BRCA-2 mutations
• Multiple clinical trials of PARP inhibitors
•
•
Pishvaian, et al
Consistent evidence of increased efficacy in BRCA-1 or -2 mutant tumors
Anecdotal evidence in pancreatic cancer
• e.g. Lowery, et al, 2011, MSKCC - 15 patients with known BRCA-1 or -2
mutations
• 4 patients with PARPi-based therapy
• 3PRs and one SD for 6 months
Rowe and Glazer Breast Cancer Research ,2010
Goggins, M, Cancer Res 1996
Murphy KM, Cancer Res 2002
Ozçelik, H, Nat Genet 1997
Lowery, et al, Oncologist, 2011
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Phase I/II Trial of 5FU, Oxaliplatin,
and ABT-888 in Pancreatic Cancer
• Phase I – ABT-888 dose escalation
• Mixture of untreated and previously treated patients
• Phase II - two strata
• Untreated vs. previously treated
Oxaliplatin
85mg/m2
Leucovorin
400mg/m2
5-FU Bolus
400mg/m2
5-FU CI
2400mg/m2
ABT-888
Orally BID
Oxaliplatin
85mg/m2
Leucovorin
400mg/m2
5-FU Bolus
400mg/m2
5-FU CI
2400mg/m2
ABT-888
Orally BID
Day 1 2 3 4 5 6 7
Cycle 1
Pishvaian, et al
15
Oxaliplatin
85mg/m2
Leucovorin
400mg/m2
5-FU Bolus
400mg/m2
5-FU CI
2400mg/m2
ABT-888
Orally BID
29
Cycle 2
Oxaliplatin
85mg/m2
Leucovorin
400mg/m2
5-FU Bolus
400mg/m2
5-FU CI
2400mg/m2
ABT-888
Orally BID
Response
Assessment
43
Cycle 3
56
Cycle 4
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Inclusion/Exclusion Criteria
•
Inclusion Criteria
•
•
•
•
•
•
Metastatic pancreatic adenocarcinoma
Measurable or evaluable disease
Adequate hepatic, bone marrow, and renal function
Age ≥ 18 years
ECOG performance status 0-2
Exclusion Criteria
• Untreated CNS metastases
• Active severe infection
• Active cardiovascular disease
• Women who were pregnant or breastfeeding
• Anticipated patient survival under 3 months
Pishvaian, et al
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Trial Design – Phase I
• Primary objective
• Recommended phase II dose
• Secondary objectives
•
•
•
•
Response rate
Progression free survival
Overall Survival
Pharmacokinetics
• Study design
• Standard 3+3 dose escalation
Pishvaian, et al
Cohort
-1
1
2
3
4
5
6
7
8
ABT-888 (mg)
20
40
60
80
100
150
200
250
300
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Results - Patients
• 01/2011 to 01/2013, 28 patients enrolled
•
62% untreated
• Median Age – 64 years
• Range 45 to 79
• 19 Male, 9 Female
• Median ECOG PS – 1
• 0 - n=7
• 1 - n=20
• 2 - n=1
• Previously treated
•
Cohort
-1
1
2
3
4
5
ABT-888 (mg)
20
40
60
80
100
150
6
7
8
200
250
300
N
6*
3
3
3
3
DLT
4#
6*
Replaced
DLT
Median number of prior chemotherapy regimens - 1.5 (Range 1-3)
Pishvaian, et al
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Adverse Events in ≥ 10%
Grade
CTCAE_Term
Nausea
Vomiting
Fatigue
Dysesthesia
Paresthesia
Neutropenia
Thrombocytopenia
Pain
Diarrhea
Lymphopenia
Constipation
Anorexia
Anemia
Cognitive disturbance
Gastroparesis
Total
Pishvaian, et al
1
11
9
6
8
7
1
4
3
3
1
3
4
2
2
2
66
2
3
1
4
0
0
4
2
1
1
2
1
0
0
1
1
21
3
0
0
0
0
0
1
0
2
1
1
0
0
1
0
0
6
5
0
0
0
0
0
1
0
0
0
0
0
0
0
0
0
1
total
14
10
10
8
7
7
6
6
5
4
4
4
3
3
3
94
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Adverse Events, ≥ Grade 3
Grade
CTCAE_Term
Neutropenia
Pain
Diarrhea
Lymphopenia
Anemia
Total
3
1
2
1
1
1
6
5
1
0
0
0
0
1
total
7
6
5
4
3
25
• Primary toxicity has been myelosuppression
• Prolonged more than severe
Pishvaian, et al
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Adverse Events – Trial Modification
• Patients 1 – 6
• Dose delayed for myelosuppression in 3 of 6 patients
• June, 2011 – 5FU bolus dropped
• Patients 7 – 22
• Dose delayed for myelosuppression in 1 of 16 patients
• Patients 23 – 26 @ ABT-888, 250mg BID
• Dose delayed for myelosuppression in 3 of 4 patients
Pishvaian, et al
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Efficacy Outcome
• As of 01-14-2013 - Analysis of 18 evaluable patients
•
•
Untreated (n = 11)
Previously Treated (n= 7)
Untreated
mOS = 7.4 months
ORR = 18% (2 cPR)
Previously Treated
mOS = 5.4 months
ORR = 14% (1 cPR)
OS
Pishvaian, et al
Untreated
mPFS = 3.9 months
Previously Treated
mPFS = 1.8 months
PFS
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Patient Numbers
Preliminary Results
BRCA-2 mutation
66
11
11
15
15
33
17
17
55
10
10
Overall Survival
Progression-Free Survival
Months – Untreated
0
Patient Numbers
0.00
14
13
4
7
15
12
2
9
2
2.00
4
4.00
6
6.00
8
8.00
10
10.00
12
14
12.00
14.00
16.00
16
18.00
18
20
20.00
BRCA-2 mutation
14
13
4
7
Overall Survival
Progression-Free Survival
16
12
Months – Previously Treated
2
9
0.00
0
2.00
2
4.00
4
6.00
6
8.00
8
10.00
10
12.00
12
14.00
14
• 2 patients with defined BRCA2 mutations
Pishvaian, et al
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Conclusions
• 5FU, Oxaliplatin, and ABT-888 has been safe to administer
• Toxicities parallel those with FOLFOX alone
• RP2D likely 200 or 250mg of ABT-888 BID
• There is evidence of anti-cancer activity:
• 3 PRs and 10 with Stable Disease
• Particular benefit in BRCA-2 mutation carriers
• Correlative studies for predictive subgroups are pending
• Good tissue acquisition rate
Pishvaian, et al
Georgetown Lombardi
PARP Inhibitor-Based Therapy
in Pancreatic Cancer
•
•
•
•
•
•
•
NCT01585805 – Gem/Cis + ABT-888
•
Eileen O’Reilly, MSKCC
NCT01233505 – CAPOX + ABT-888
•
William Schelman, University of Wisconsin
NCT01366144 – Carbo/Taxol + ABT-888
hepatorenal dysfunction
•
Hussein Tawbi, University of Pittsburgh
NCT01281150 – Carbo/Taxol + ABT-888
•
Chandra P. Belani, Penn State
NCT00892736 – ABT-888 Single agent
•
Edward Chu, U. Penn
NCT01154426 – Gemcitabine + ABT-888
•
Ronald Stoller, University of Pittsburgh
NCT00576654 – Irinotecan + ABT-888
•
Patricia LoRusso, Karmanos Cancer Institute
Pishvaian, et al
•
•
•
•
•
NCT01296763 – Irinotecan, Cisplatin, Mitomycin C
+ Olaparib
•
Michael Goggins, Johns Hopkins
NCT01286987 – BMN 673 single agent
•
Andrew Dorr, BioMarin Pharmaceutical
NCT01482715 – Rucaparib single agent
•
Clovis Oncology, Inc.
NCT01009190 - PF-01367338 + various
chemotherapies
•
Clovis Oncology, Inc.
NCT01618136 - E7449 + temozolomide OR
carbo/taxol
•
Eisai, Inc
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Acknowledgments
• Otto J. Ruesch Center for the Cure of GI Cancer
• The patients and their families
•
Biostatisticians
•
•
•
Tingting Zhuang, MS
Hongkun Wang, PhD
Clinical Care and CRMO
•
•
•
•
•
•
•
John Marshall, MD
Louis M. Weiner, MD
Jimmy Hwang, MD
A. Ruth He, MD, PhD
Amy Hankin, PA
Lisa Ley, RN
Keisha White, RN
• Thomas Jefferson
• Jonathan Brody, PhD
• Susan Littman, MD
• Patient #14
• Ben Tan, M.D., Wash U.
• Robert Wolff, M.D., MDACC
• Indivumed
• Nina Gabelia, MD, MPH
• Lana Kapanadze, MS
• HTSR - Lombardi
• Deborah Berry, PhD
• Abbott
• Meeta Jaiswal, PhD
Pishvaian, et al
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