Presented at the American Society of Clinical Oncology, Chicago, IL, May 30June 3, 2014

Veliparib in combina on with FOLFIRI chemotherapy was generally well tolerated without drug-drug PK interac ons. The RP2D is veliparib 200 mg BID with bimonthly FOLFIRI (irinotecan 150 or 180 mg/m2 without 5-FU bolus). Pa ents with ovarian and breast cancer experienced the greatest an tumor ac vity, with an ORR of 38% and 22%, respec vely, but prior treatments/

exposures and/or BRCA status could have infl uenced these results. This study supports further evalua on of veliparib in combina on with FOLFIRI in several tumor types.

CONCLUSIONS

A Phase 1 Dose-Escala on Study of Veliparib With Bimonthly FOLFIRI in Pa ents With Advanced Solid Tumors Jordan Berlin1, Ramesh K. Ramanathan2, John H. Strickler3, Deepa Suresh Subramaniam4, Herbert Hurwitz3, Yoon-Koo Kang5, Tae-You Kim6, Stacie Peacock Shepherd7, Hao Xiong7, Robert Hetman7, Caroline Nickner7, Ma hew W. Dudley7, Vincent L. Giranda7, Heinz-Josef Lenz8 1Vanderbilt-Ingram Cancer Center, Nashville, TN, USA; 2Transla onal Genomics Research Ins tute Virginia G. Piper Cancer Center, Sco sdale, AZ, USA; 3Duke University Medical Center, Durham, NC, USA; 4Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA; 5Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea;6Department of Internal Medicine and Cancer Research Ins tute, Seoul Na onal University Hospital, Seoul Na onal University College of Medicine, Seoul, South Korea; 7AbbVie Inc., North Chicago, IL, USA; 8Division of Medical Oncology, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA

2574

INTRODUCTION

To view an electronic version of this poster, scan QR code or visit abbviescience.com/614119315/6

OBJECTIVE

METHODS

RESULTS

ACKNOWLEDGEMENTSThis presenta on was supported by AbbVie. AbbVie par cipated in the design and conduct of the study and in the analysis and interpreta on of the data as well as the wri ng, review, and approval of the poster. Medical wri ng support was provided by Jennifer Han of Complete Publica on Solu ons, LLC; this support was funded by AbbVie.

1. Chiarugi A. Trends Pharmacol Sci. 2002;23(3):122-129.2. Virag L and Szabo C. Pharmacol Rev. 2002;54(3):375-429.3. Cur n NJ, et al. Clin Cancer Res. 2004;10(3):881-889.4. Davidson D, et al. Invest New Drugs. 2013;31(2):461-468.5. Shelton JW, et al. Int J Radiat Oncol Biol Phys. 2013;86(3):469-476.6. Goodman SN, et al. Stat Med. 1995;14(11):1149-1161.7. OQuigley J and Zohar S. Br J Cancer. 2006;94(5):609-613.8. Piantadosi S, et al. Cancer Chemother Pharmacol. 1998;41(6):429-436.9. Eisenhauer EA, et al. Eur J Cancer. 2009;45(2):228-247.

REFERENCESDISCLOSURES

Jordan Berlin, Heinz-Josef Lenz, Ramesh K. Ramanathan and John Strickler received research funding from AbbVie. Yoon-Koo Kang and Tae-You Kim have no confl icts to disclose. Deepa Subramaniam, Stacie Shepherd, Hao Xiong, Robert Hetman, Caroline Nickner, Ma Dudley, and Vincent Giranda are AbbVie employees and may hold AbbVie stock or op ons.

Poly(ADP-ribose) polymerase (PARP)-1 and PARP-2 are nuclear enzymes that recognize DNA damage and facilitate DNA repair.1,2

Gene c defi ciencies and the ac on of DNA-damaging chemotherapies render cancer cells more dependent on PARP-1 and PARP-2 for DNA repair and therefore more sensi ve to PARP inhibi on.3

Veliparib (ABT-888) is a potent, oral, compe ve PARP-1 and PARP-2 inhibitor that enhances the ac vity of genotoxic agents, such as irinotecan, in preclinical tumor models (Figure 1).4,5

Figure 1. Veliparib + Irinotecan in a Preclinical Model

Veliparib (ABT-888) and/or irinotecan (irino) was administered to 14 groups of 10 mice in a HCT116 model of human colorectal carcinoma.

To determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of veliparib in combina on with various regimens of bimonthly folinic acid + 5-fl uorouracil (5-FU) + irinotecan (FOLFIRI) in pa ents with solid tumors

STUDY DESIGN This ongoing, phase 1, open-label, mul center, dose-escala ng study

included dose-escala on and safety-expansion phases in which pa ents received veliparib and bimonthly FOLFIRI in 28-day cycles (Figure 2).

Veliparib was administered on Days 1519 in Cycle 1 and on Days 15 and 1519 in subsequent cycles.

Subjects with stable disease or be er status could con nue veliparib and FOLFIRI un l progressive disease (PD), unacceptable toxicity, or FOLFIRI discon nua on.

Figure 2. Study Design

Part 1n = 67

Velipariba 10, 20, 40, 80, or130 mg BID

+Folinic acid 400 mg/m2 2-h infusion

+5-FU 2400 mg/m2 46-h infusion

+Irinotecan 150 mg/m2 90-min infusion

Part 2n = 8

Velipariba 160, 200, or 270 mg BID+

Folinic acid 400 mg/m2 2-h infusion+

5-FU 2400 mg/m2 46-h infusion [+ bolus]

+Irinotecan 150 mg/m2 90-min infusion

Part 3n = 25

Velipariba 100, or 200 mg BID+

5-FU 2400 mg/m2 46-h infusion [no bolus]

+Irinotecan 180 mg/m2 90-min infusion

W>d>d

WWZWd

W>d W>d>d

WWZWd

dN = 92

FOLFIRI = folinic acid + 5-fl uorouracil + irinotecan; PARP = Poly(ADP-ribose) polymerase.aThe bolus 5-FU dose was not tolerated during the fi rst 2 weeks of C1, before veliparib administra on. P2 dose escala on was consequently discon nued and, although pa ents could con nue veliparib, they were considered not evaluable. Data from Part 2 were combined with those from Part 3.

METHODS CONTINUEDTable 1. Key Study Entry Criteria

All Patients

Age 18 years Eastern Cooperative Oncology Group performance status score of 01

Received 3 prior DNA-damaging agents/cytotoxic chemotherapy within the past 2 years Dose Escalation Safety Expansion

Patients with histologically/cytologically confi rmed solid tumors that are metastatic or unresectable and 1 of the following:

Patients with histologically confi rmed, advanced/metastatic cancer with irinotecan-based regimen as standard therapy

- FOLFIRI as a viable option - ~50% of whom have histologically confi rmed gastric cancer and no previous treatment with a PARP inhibitor- No standard curative/therapeutic options

- Refractory disease to standard therapy

DOSE ESCALATION AND DETERMINATION OF MTD AND RP2D Dose escala on was conducted in 3 parts; a minimum of 3 pa ents per

dose level were included for dose-toxicity modeling: Part 1 (P1) regimen: Dose escala on began with veliparib 10 mg twice daily (BID) + bimonthly FOLFIRI (folinic acid + 5-FU + irinotecan 150 mg/m2)

Part 2 (P2) regimen: Veliparib 160 mg BID + bimonthly FOLFIRI (folinic acid + 5-FU [+bolus] + irinotecan 150 mg/m2)

Part 3 (P3) regimen: Veliparib with dose escala on star ng at 100 mg BID or MTD + bimonthly FOLFIRI (5-FU + irinotecan 180 mg/m2) without bolus 5-FU

Folinic acid was administered as 400 mg/m2 over 2 hours on Days 1 and 15 and con nuous infusion 5-FU was administered at a dose of 2400 mg/m2 over 46 hours beginning on Days 1 and 15

A con nual reassessment method6-8 that uses Bayesian methods to incorporate informa on from all prior events (e.g., doses and tolerability) into a dose-response model in real me guided dose escala on.

Dose-escala on pa ents who did not require FOLFIRI dose reduc on by Cycle (C) 1 Day (D) 15 were evaluated for DLT in the second half of C1; those who required dose reduc on were replaced to ensure 3 evaluable pa ents per dose cohort.

MTD was defi ned as the largest dose for which the probability of DLT was 3 47 (51)

Patients who received cisplatin or carboplatin, n (%) 42 (46)Patients who received oxaliplatin, n (%) 44 (48)Median (range) prior lines of therapy

Overall group (n = 92) 3 (0-10)Patients with colorectal cancer (n = 6) or gastric cancer (n = 14)

1.5 (0-4)

Median (range) cycles of veliparib 4 (1-48)*Other types of tumor include: esophageal (n = 4); head and neck (n = 2); hepatocellular carcinoma (n = 1); non-small cell lung cancer (n = 3); other adenocarcinoma (n = 1); other adenoid cys c tumor (n = 1); other cholangiocarcinoma (n = 2); other common bile duct tumor (n = 1); other malignant neoplasm (n = 1); other papillary serous tumor (n = 1); other pseudomyxoma peritonea (n = 1);other squamous carcinoma (n = 1); other unknown primary tumor (n = 1); skin cancer (n = 1); small cell lung cancer (n = 2).

SAFETY 86 pa ents discon nued veliparib: 83 due to PD, 7 withdrew consent,

3 due to adverse events (1 PD-related), and 9 for other reasons. (Pa ents who discon nued study drug are counted under each reason given for discon nua on. Therefore, the sum of the counts given for the reasons may be greater than the overall number of discon nua ons).

Adverse events and grade 3/4 toxici es that occurred in 30% pa ents overall are reported in Table 3.

Table 3. Treatment-Emergent Adverse Events Reported in 30% of All Pa ents

Part 1n = 67

Parts 2a and 3 n = 25

Combined RP2Db n = 31

TotalN = 92

Adverse EventsAll

Grades Grade

3/4All

Grades Grade

3/4All

Grades Grade

3/4All

Grades Grade

3/4Diarrhea 60 36 68 28 58 29 62 34Neutropenia 57 43 72 60 77 68 61 48Nausea 61 40 56 32 71 52 60 38Vomiting 48 28 48 24 45 23 48 27Fatigue 39 25 68 44 42 29 47 30Anemia 39 22 52 28 45 29 42 24Alopecia 45 25 28 4 45 26 40 20Decreased appetite 15 9 52 28 23 16 33 15

RP2D = recommended phase 2 dose.a Pa ents in Part 2 did not tolerate the 5-FU bolus as part of the FOLFIRI regimen. Therefore, dose escala on was discon nued and, although pa ents could con nue veliparib, they were considered not evaluable. Data from the 8 pa ents in Part 2 were combined with Part 3.b Includes 20 pa ents from Part 1 and 11 pa ents from Part 3.

Grade 3/4 toxici es that were considered possibly or probably related to veliparib (in 2% of the overall study popula on) included neutropenia (29%), anemia (4%), febrile neutropenia (3%), dehydra on (2%), diarrhea (2%), leukopenia (2%), and vomi ng (2%).

DLTS AND RP2D Four DLTs occurred: 3 DLTs of neutropenia (at veliparib 160 and 270 mg

BID in P1, and at veliparib 100 mg BID in P2) and 1 DLT of gastri s and vomi ng (at veliparib 270 mg BID in P1).

In P2, the 5-FU bolus of the FOLFIRI regimen was not tolerated during the fi rst 2 weeks of C1, before veliparib administra on. P2 dose escala on was consequently discon nued, and P2 was moved into P3.

The RP2D was determined to be veliparib 200 mg BID in both P1 and P3. 2 safety-expansion cohorts were enrolled at the RP2D + FOLFIRI with

either irinotecan 150 mg/m2 (gastric cancer, n = 14) or 180 mg/m2 (colorectal cancer, n = 7).

PHARMACOKINETICS Veliparib exposure was approximately dose propor onal in combina on

with FOLFIRI (Figure 3). Veliparib PK parameters are comparable to those in other ongoing

veliparib phase 1 studies, sugges ng no signifi cant e ect of FOLFIRI on veliparib PK.

Irinotecan/SN-38, folinic acid (leucovorin), and 5-FU PK were comparable with or without veliparib administra on.

Figure 3. Mean SD Cmax and AUC08 of Veliparib A er a Single Dose of Veliparib in Combina on With FOLFIRI

0 50 100 150 200 250 3000.00

0.25

0.50

0.75

1.00

1.25

1.50

1.75

0 50 100 150 200 250 3000123456789

Veliparib Dose (mg) 10 20 40 80 100 130 160 200 270N 10 5 5 4 11 4 9 4 5

Veliparib Dose (mg) Veliparib Dose (mg)

AUC 0

-8 (

gh/

mL)

C max

(g/

mL)

AUC08 = area under the plasma concentra on- me curve from me 0 to 8 hours; Cmax = maximum observed plasma concentra on.

EXPLORATORY EFFICACY Response rates, mes to disease progression, and best percentage

change from baseline in tumor size by veliparib dose are shown by tumor type in Table 4 and Figures 4 and 5, respec vely.

Table 4. ORR and TTP RateOvarian

n = 8Breast n = 9

Pancreatic n = 14

Gastric n = 20

Colorectal n = 10

Other n = 30

ORRa (CR+PR), n (%) [95% CI]

3 (38) [8.575.5]

2 (22) [2.860.0]

2 (14) [1.842.8]

3 (15) [3.237.9]

1 (10) [0.344.5]

2 (7) [0.822.1]

PR, n 3 2 2 3 1 2TTP rateb at 6 mo [95% CI]

63.5 [23.886.6]

22.2 [3.451.3]

26.8 [7.351.5]

45.9 [22.866.4]

50.8 [15.778.1]

21.9 [8.239.8]

CR = complete response; ORR = objec ve response rate; PR = par al response; TTP = me to progression.a ORR was es mated for all pa ents with 1 measurable lesion; the corresponding 95% CI was constructed using exact binomial distribu on.b The distribu on of TTP was es mated using Kaplan-Meier methodology.One ovarian pa ent was unevaluable.

The median TTP was longest in pa ents with ovarian cancer at 361 days, with the upper bound of the 95% CI not reached (Figure 4A). The median TTP was 195 and 157 days, respec vely, in pa ents with colorectal or gastric cancer (Figure 4B).

Figure 4. Kaplan-Meier Curve for Time to Disease Progressiona (A) Pa ents With Breastb, Ovarianb, or Other Cancer and for (B) Pa ents With Colorectal, Gastricc, or Pancrea c Cancer in the Dose-Escala on and Safety-Expansion Cohorts

Prob

abili

ty o

f Rem

aini

ng

Prog

ress

ion-

free

1.00.90.80.70.60.50.40.30.20.10.0

OvarianBreastOther Censored

Days Since First Dose11401020960900840780720660600540480420360300240180120600 1080

Pt at RiskOvarian 9 7 6 5 4 3 3 2 2 2 2 2 2 2 2 2 2 2 1 1Breast 9 6 4 2 2 2 2 2 2 2 2 2 2 0Other 30 21 12 5 3 3 3 3 3 3 1 1 0

Ovarian Breast Other (N = 9) (N = 9) (N = 30)Event (%) 6 (66.7) 9 (100.0) 25 (83.3)Median Days (95% CI) 361 (1, - ) 107 (36, 730) 113 (92, 154)

Prob

abili

ty o

f Rem

aini

ng

Prog

ress

ion-

free

1.00.90.80.70.60.50.40.30.20.10.0

GastricColorectalW

Censored

Days Since First Dose780720660600540480420360300240180120600

Pt at RiskGastric 20 10 9 7 6 6 4 3 1 1 0Colorectal 10 8 4 4 1 1 0W

' W (N = 20) (N = 10) (N = 14)Event (%) 13 (65.0) 6 (60.0) 13 (92.9)Median Days (95% CI) 157 (51, 568 ) 195 (43, -) 42 (32, 295)

A. B.

a The distribu on of me to progression (median me to progression and corresponding 95% CI) was es mated using Kaplan-Meier methodology.b 4 pa ents with breast cancer and 4 pa ents with ovarian cancer were BRCA+.c Median PFS was longer in the safety-expansion cohort for gastric cancer pa ents at 223 (95% CI, 57, not reached).

The majority of safety-expansion pa ents experienced some reduc on in tumor size from baseline (Figure 5A and B).

Figure 5. Best Percentage Change From Baseline in Tumor Size by Veliparib Dose for A) Pa ents With Breast, Ovarian, or Other Cancer and for B) Pa ents With Colorectal, Gastric, or Pancrea c Cancer in the Dose-Escala on and Safety-Expansion Cohorts

-100

-75

-50

-25

0

25

50

75

Best

Per

cent

Cha

nge

From

Bas

elin

e

Breast(N = 8)

Ovarian (N = 6)

Other (N = 23)

10 mg (non-bolus)10 mg (bolus)20 mg40 mg80 mg100 mg (non-bolus100 mg (bolus)

130 mg160 mg200 mg (150 mg/m2 irinotecan)200 mg (180 mg/m2 irinotecan)270 mg300 mg

* *

*

*

*

*

**

*

*

A.

Colorectal(N = 11)

Gastric (N = 19)

Pancreac(N = 13)

-100

-75

-50

-25

0

25

50

75

Best

Per

cent

Cha

nge

From

Bas

elin

e

10 mg (non-bolus)10 mg (bolus)20 mg40 mg80 mg100 mg (non-bolus100 mg (bolus)

130 mg160 mg200 mg (150 mg/m2 irinotecan)200 mg (180 mg/m2 irinotecan)270 mg300 mg

*

*

**

B.

Bolus = 5-FU bolus as part of the FOLFIRI regimen; Non-bolus = no 5-FU bolus as part of the FOLFIRI regimen. Evaluable pa ents had at least one CT scan following the start of therapy.*BRCA+.

NCT01123876