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 + A Phase I/II Study of ABT-888, 5- fluorouracil and oxaliplatin in patients with metastatic pancreatic cancer *Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC + Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA
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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.
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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+
A Phase I/II Study of ABT-888, 5-fluorouracil and oxaliplatin in patients with metastatic
pancreatic 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 related to this work
Pishvaian, et al Georgetown Lombardi
Metastatic Pancreatic Cancer
• Survival rates are poor• FOLFIRINOX • Gemcitabine + Abraxane• But OS still <1 year
• Novel Targets• DNA damage control?
Conroy, et al, NEJM, 2011Von Hoff, JCO, 2011
Jones, et al, Science. 2008Pishvaian, et al Georgetown Lombardi
Is there a therapeutic opportunity here?
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 /ASCO, 2009 Helleday T, et al. Nat Rev Cancer, 2008
Inhibition of PARP• Prevents recruitment of DNA repair enzymes• Leads to failure of single strand break repair
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 DeathPishvaian, et al Georgetown Lombardi
PARP Inhibition Increases Pancreatic Cancer Cell Sensitivity to Chemotherapy
• Exogenous mutant PARP
increased sensitivity to oxaliplatin
• 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
Brody, et al, unpublished dataDonawho, CK, et al, Clin Cancer Res 2007
Palma, JP, et al, Clin Cancer Res 2009Kummar, S, et al, JCO. 2009Pishvaian, et al Georgetown Lombardi
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• 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 ,2010Goggins, M, Cancer Res 1996Murphy KM, Cancer Res 2002
Ozçelik, H, Nat Genet 1997Lowery, et al, Oncologist, 2011Pishvaian, et al Georgetown Lombardi
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
Pishvaian, et al Georgetown Lombardi
1 2 3 4 5 6 7 2915 43 56
Cycle 4Cycle 1 Cycle 3Cycle 2
Day
ResponseAssessment
5-FU CI2400mg/m2
ABT-888Orally BID
5-FU CI2400mg/m2
ABT-888Orally BID
5-FU CI2400mg/m2
ABT-888Orally BID
Oxaliplatin85mg/m2
Leucovorin400mg/m2
Oxaliplatin85mg/m2
Leucovorin400mg/m2
Oxaliplatin85mg/m2
Leucovorin400mg/m2
Oxaliplatin85mg/m2
Leucovorin400mg/m2
5-FU CI2400mg/m2
ABT-888Orally BID
5-FU Bolus400mg/m2
5-FU Bolus400mg/m2
5-FU Bolus400mg/m2
5-FU Bolus400mg/m2
• 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 pancreatic adenocarcinoma• Measurable or evaluable disease• Adequate hepatic, bone marrow, and renal function • Age ≥ 18 years• ECOG performance status 0-2