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M. J. Pishvaian * , H. Wang *, T. Zhuang *, A. R. He*,

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 +.

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M. J. Pishvaian * , H. Wang *, T. Zhuang *, A. R. He*,

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  1. 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

  2. Financial Disclosures Pishvaian, et al • 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 Georgetown Lombardi

  3. Pishvaian, et al 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? Conroy, et al, NEJM, 2011 Von Hoff, JCO, 2011 Jones, et al, Science. 2008 Georgetown Lombardi

  4. 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 Pishvaian, et al 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 Georgetown Lombardi Tutt, A, et al, JCO /ASCO, 2009 Helleday T, et al. Nat Rev Cancer, 2008

  5. PARP Inhibition Increases Pancreatic Cancer Cell Sensitivity to Chemotherapy Pishvaian, et al • 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 data Donawho, CK, et al, Clin Cancer Res 2007 Palma, JP, et al, Clin Cancer Res 2009 Kummar, S, et al, JCO. 2009 Georgetown Lombardi

  6. 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 Pishvaian, et al 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 Georgetown Lombardi

  7. Phase I/II Trial of 5FU, Oxaliplatin, and ABT-888 in Pancreatic Cancer Pishvaian, et al • Phase I – ABT-888 dose escalation • Mixture of untreated and previously treated patients • Phase II - two strata • Untreated vs. previously treated Oxaliplatin 85mg/m2 Oxaliplatin 85mg/m2 Oxaliplatin 85mg/m2 Oxaliplatin 85mg/m2 Leucovorin 400mg/m2 Leucovorin 400mg/m2 Leucovorin 400mg/m2 Leucovorin 400mg/m2 5-FU Bolus 400mg/m2 5-FU Bolus 400mg/m2 5-FU Bolus 400mg/m2 5-FU Bolus 400mg/m2 5-FU CI 2400mg/m2 5-FU CI 2400mg/m2 5-FU CI 2400mg/m2 5-FU CI 2400mg/m2 ABT-888 Orally BID ABT-888 Orally BID ABT-888 Orally BID ABT-888 Orally BID Response Assessment Day 1 2 3 4 5 6 7 15 29 43 56 Cycle 1 Cycle 2 Cycle 3 Cycle 4 Georgetown Lombardi

  8. Metastatic pancreatic adenocarcinoma Measurable or evaluable disease Adequate hepatic, bone marrow, and renal function Age ≥ 18 years ECOG performance status 0-2 Pishvaian, et al 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 Georgetown Lombardi

  9. Trial Design – Phase I Pishvaian, et al • Primary objective • Recommended phase II dose • Secondary objectives • Response rate • Progression free survival • Overall Survival • Pharmacokinetics • Study design • Standard 3+3 dose escalation Georgetown Lombardi

  10. Pishvaian, et al 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 • Median number of prior chemotherapy regimens - 1.5 (Range 1-3) DLT Replaced DLT Georgetown Lombardi

  11. Adverse Events in ≥ 10% Pishvaian, et al Georgetown Lombardi

  12. Adverse Events, ≥ Grade 3 Pishvaian, et al • Primary toxicity has been myelosuppression • Prolonged more than severe Georgetown Lombardi

  13. Adverse Events – Trial Modification Pishvaian, et al • 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 Georgetown Lombardi

  14. Efficacy Outcome Pishvaian, et al • 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) • Untreated • mPFS = 3.9 months • PreviouslyTreated • mOS = 5.4 months • ORR = 14% (1 cPR) • PreviouslyTreated • mPFS = 1.8 months OS PFS Georgetown Lombardi

  15. Overall Survival Overall Survival Progression-Free Survival Progression-Free Survival Pishvaian, et al Preliminary Results 14 13 4 7 16 12 6 • BRCA-2 mutation 2 11 9 15 0.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00 Patient Numbers 3 17 5 Months – Untreated 10 0 2 4 6 8 10 12 14 16 18 20 14 • BRCA-2 mutation 13 4 7 Patient Numbers 15 12 2 Months – Previously Treated 9 0 2 4 6 8 10 12 14 • 2 patients with defined BRCA2 mutations Georgetown Lombardi

  16. Pishvaian, et al 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 Georgetown Lombardi

  17. PARP Inhibitor-Based Therapy in Pancreatic Cancer Pishvaian, et al • 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 • 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 Georgetown Lombardi

  18. Biostatisticians TingtingZhuang, 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 MeetaJaiswal, PhD Pishvaian, et al Acknowledgments • Otto J. Ruesch Center for the Cure of GI Cancer • The patients and their families Georgetown Lombardi

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