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

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

0 10 20 30 400.0

0.5

1.0Emty VectorPARP.R355D(Mut)PARP.E988A(Mut)PARP.W318R(Mut)

100

50

0

M Oxaliplatin

% s

urv

ivin

g c

ells

0 2 4 60.0

0.5

1.0 Cisplatin aloneABT-888+ Cisplatin

100

50

0

M Cisplatin

% s

urv

ivin

g c

ells

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


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


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


Cohort ABT-888 (mg) -1 201 402 603 804 1005 1506 2007 2508 300

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)


Cohort ABT-888 (mg) N-1 20 1 40 6*2 60 33 80 34 100 35 150 3

6 200 4#

7 250 6*8 300

DLT

DLT

Replaced

Adverse Events in ≥ 10%


1 2 3 5 totalNausea 11 3 0 0 14Vomiting 9 1 0 0 10Fatigue 6 4 0 0 10Dysesthesia 8 0 0 0 8Paresthesia 7 0 0 0 7Neutropenia 1 4 1 1 7Thrombocytopenia 4 2 0 0 6Pain 3 1 2 0 6Diarrhea 3 1 1 0 5Lymphopenia 1 2 1 0 4Constipation 3 1 0 0 4Anorexia 4 0 0 0 4Anemia 2 0 1 0 3Cognitive disturbance 2 1 0 0 3Gastroparesis 2 1 0 0 3Total 66 21 6 1 94

CTCAE_TermGrade

Adverse Events, ≥ Grade 3


• Primary toxicity has been myelosuppression• Prolonged more than severe

3 5 totalNeutropenia 1 1 7Pain 2 0 6Diarrhea 1 0 5Lymphopenia 1 0 4Anemia 1 0 3Total 6 1 25

CTCAE_TermGrade

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

Efficacy Outcome


OS PFS

Untreated

mOS = 7.4 months

ORR = 18% (2 cPR)

• As of 01-14-2013 - Analysis of 18 evaluable patients• Untreated (n = 11)

• Previously Treated (n= 7)

Previously Treated

mOS = 5.4 months

ORR = 14% (1 cPR)

Untreated

mPFS = 3.9 months

Previously Treated

mPFS = 1.8 months

0.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00

9

2

12

16

7

4

13

14

Preliminary Results

0.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00 18.00 20.00

10

5

17

3

15

11

6

• 2 patients with defined BRCA2 mutations

Months – Untreated

Overall Survival

Progression-Free Survival

Months – Previously Treated

BRCA-2 mutation

BRCA-2 mutation


Overall Survival

Progression-Free Survival

2 4 6 8 10 12 14 16 18 200

6

11

153

17

5

10

1413

47

1512

29

2 4 6 8 10 12 140

Pat

ient

Num

bers

Pat

ient

Num

bers

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 ratePishvaian, 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


• 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

Acknowledgments

• 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

• Otto J. Ruesch Center for the Cure of GI Cancer• The patients and their families


Documents

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

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