M.%20J.%20Pishvaian*,%20H.%20Wang*,%20T.%20Zhuang*,%20A.%20R.%20He*,

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

• 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

3
Metastatic Pancreatic Cancer

• Survival rates are poor
• FOLFIRINOX
• Gemcitabine Abraxane
• But OS still lt1 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
4
Mechanisms of DNA Repair PARP (Poly(ADP-ribose)
polymerase)
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
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

• 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Brody, et al, unpublished data Donawho, CK, et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
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

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
7
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

1
2
3
4
5
6
7
29
15
43
56
Day
Cycle 4
Cycle 1
Cycle 3
Cycle 2
8
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

• Metastatic pancreatic adenocarcinoma
• Measurable or evaluable disease
• Adequate hepatic, bone marrow, and renal function
  
• Age 18 years
• ECOG performance status 0-2

9
Trial Design Phase I

• Primary objective
• Recommended phase II dose
• Secondary objectives
• Response rate
• Progression free survival
• Overall Survival
• Pharmacokinetics
• Study design
• Standard 33 dose escalation

10
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 - n7
• 1 - n20
• 2 - n1
• Previously treated
• Median number of prior chemotherapy regimens -
  1.5 (Range 1-3)

DLT
Replaced
DLT
11
Adverse Events in 10
12
Adverse Events, Grade 3

• Primary toxicity has been myelosuppression
• Prolonged more than severe

13
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 _at_ ABT-888, 250mg BID
• Dose delayed for myelosuppression in 3 of 4
  patients

14
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)
Untreated mPFS 3.9 months
Previously Treated mOS 5.4 months ORR 14 (1
cPR)
Previously Treated mPFS 1.8 months
OS
PFS
15
Preliminary Results
6
BRCA-2 mutation
11
15
Patient Numbers
3
17
5
Months Untreated
10
2
4
6
8
10
12
14
16
18
20
0
14
BRCA-2 mutation
13
4
7
Patient Numbers
15
12
2
Months Previously Treated
9
2
4
6
8
10
12
14
0

• 2 patients with defined BRCA2 mutations

16
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

17
PARP Inhibitor-Based Therapy in Pancreatic Cancer

• NCT01585805 Gem/Cis ABT-888
• Eileen OReilly, 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

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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