Efficacy of BSI-201, a PARP Inhibitor,in Combination with

Gemcitabine/Carboplatin in Triple Negative Metastatic Breast Cancer:

Results of a Phase II StudyJoyce O’Shaughnessy,1,2,4 Cynthia Osborne,1,2,4 John Pippen,1,2,4, Debra

Patt,3,4

Christine Rocha,5 Valeria Ossovskaya,5 Barry M. Sherman,5 Charles

Bradley 5

1Baylor Sammons Cancer Center, 2Texas Oncology, Dallas, TX; 3Texas Oncology Cancer Center, Austin, Texas; 4US Oncology, Dallas, TX;

5BiPar Sciences, Inc., Brisbane, CA

Disclosure

Dr. O’Shaughnessy has no commercial relationships to disclose.

2

Replication Lesions

• Base excision repair

• PARP1

Mechanisms of DNA Repair

Single Strand Breaks• Nucleotide excision

repair• Base excision repair

• PARP1

Double Strand Breaks• Non-homologous end-joining• Homologous recombination

• BRCA1/BRCA2

• Fanconi anemia pathway• Endonuclease-mediated

repair

DNA DAMAGE

Cell Death

Environmental factors(UV, radiation, chemicals)

Normal physiology(DNA replication, ROS)

MAJOR DNA REPAIRPATHWAYS

Chemotherapy(alkylating agents, antimetabolites)

Radiotherapy

DNA Adducts/Base Damage

• Alkyltransferases• Nucleotide excision repair• Base excision repair

• PARP1

Helleday et al. Nature Reviews. 2008; 8:193 3

BRCA-Deficient Cells are Sensitive to PARP Inhibition

PARP inhibition selectively reduces viability and induces chromosomal aberrations in BRCA-deficient cells

Adapted by permission from Macmillan Publishers Ltd: Farmer et al. Nature, 2005; 434:917, © 2005

Lo

g s

urv

ivin

g f

ract

ion

Conc. PARP Inhibitor (M)

Wild type

BRCA1-/-

+ PARP Inhibitor(10 nM)

+ PARP Inhibitor(1000 nM)

No Treatment

BRCA1-Deficient Cells

BRCA1+/-

4

Triple Negative Breast Cancer (TNBC)• ER-negative, PR-negative, and HER2 not overexpressed

• ~15% of all breast cancers (~170,000 cases worldwide in 2008)1,2

• Aggressive natural history

– Higher rates of symptomatic visceral and brain metastases

– Median survival of 13 months after developing metastases3,4

– 30% patients develop metastatic disease5

4 Lin NU et al. Cancer. 2008; 113:2638-455 Rody A et al. Breast. 2007; 16:235-40

1 Carey L et al. JAMA. 2006; 295:2492-5022 Swain S. ASCO Annual Meeting. June 3, 20083 Kassam F et al. Clin Breast Cancer. 2009; 9:29-33 5

Characteristics Hereditary BRCA1 Triple Negative/Basal-Like1,2,3

ER/PR/HER2 status Negative Negative

TP53 status Mutant Mutant

BRCA1 status Mutational inactivation* Diminished expression*

Gene-expression pattern Basal-like Basal-like

Tumor histologyPoorly differentiated

(high grade)Poorly differentiated

(high grade)

Chemosensitivity to DNA-damaging agents

Highly sensitive Highly sensitive

TNBC Shares Clinical and Pathologic Features with BRCA1-Related Breast Cancers

3Sorlie et al. Proc Natl Acad Sci U S A 2001;98:10869-744 Miyoshi et al. Int J Clin Oncol 2008;13:395-400

*BRCA1 dysfunction due to germline mutations, promoter methylation, or overexpression of HMG or ID44

1Perou et al. Nature. 2000; 406:747-7522Cleator et al.Lancet Oncol 2007;8:235-44 6

• Limited treatment options for metastatic TNBC

– Most patients treated with adjuvant anthracycline, taxane, and cyclophosphamide

– PFS ≤ 4 months with chemotherapy for metastatic disease1

– Bevacizumab/paclitaxel improves PFS compared with paclitaxel alone2

• Rationale for gemcitabine/carboplatin in MBC

– Synergistic antitumor activity between gemcitabine and carboplatin3

– Active combination in MBC, with response rates from 21% to 53%3,4

Current Treatment for TNBC

3 Hsiao LC and Russell CA. Oncology. 2004; 18:124 Loesch D Et al. Clin Breast Cancer. 2008; 8:178 7

1 Kassam F et al. Clin Breast Cancer. 2009; 9:29-33 2 Miller K et al. NEJM. 2007; 357:2666

PARP Inhibitor Mechanism of Action

BRCA1BRCA2

1. PLATINUM CHEMOTHERAPY

Inflicts DNA damage via adducts and DNA crosslinking

2. PARP1UPREGULATION

Base-excision repair of DNA damage

3. INHIBITION OF PARP1

Disables DNA base-excision repair

4. REPLICATION FORK COLLAPSE

Double strand DNA break

CELL SURVIVAL CELL DEATH

PARP1

PARP1

BSI-201

Pt

Pt

Pt

Pt

Pt

PARP1

8

Preclinical Evidence for Synergy: Combination of BSI-201 with Carboplatin or GemcitabineBSI-201 potentiated antitumor effects of carboplatin and gemcitabine in the MDA-MB-468 triple negative breast cancer cell line

BiPar Sciences, data on file

Carboplatin Gemcitabine

[BSI-201] [BSI-201]

0 M 0 M50 M 50 M100 M 100 M

% V

iab

le C

ells

% V

iab

le C

ells

100 100

40 40

20 20

8080

0 0

6060

0 mM

25 mM0 nM

5 nM

9

PARP Inhibitor-Based Therapy for TNBCBackground and Rationale

• PARP1 – Upregulated in majority of triple negative human breast

cancers1

• BSI-201

– Small molecule PARP inhibitor

– Potentiates effects of chemotherapy-induced DNA damage

– No dose-limiting toxicities in Phase I studies of BSI-201 alone or in combination with chemotherapy

– Marked and prolonged PARP inhibition in PBMCs

1BiPar Sciences, data on file 10

Phase II TNBC Study• Trial Design

– Multi-center, open-label, randomized safety and efficacy trial

– 1:1 randomization of gemcitabine/carboplatin with or without BSI-201

• Primary Objectives

– Clinical benefit rate (CBR = CR + PR + SD ≥ 6 months) of gemcitabine/carboplatin ± BSI-201

– Safety of BSI-201

• Secondary Objectives– Overall response rate (ORR)

– Progression-free survival (PFS)

– Overall survival (OS)

11

Key Inclusion/Exclusion Criteria

• Histologically documented TNBC

• Metastatic breast cancer with measurable disease

• 0-2 prior chemotherapy regimens for metastatic

disease

• No prior treatment with gemcitabine, carboplatin, cisplatin, or PARP inhibitor

• Stable brain metastases allowed

• ECOG PS 0 - 1

12

Phase II TNBC Study: Treatment Schema

21-DayCycle

* Patients randomized to gem/carbo alone could crossover to receive gem/carbo + BSI-201 at disease progression

RANDOMIZE

BSI-201 (5.6 mg/kg, IV, d 1, 4, 8, 11)

Gemcitabine (1000 mg/m2, IV, d 1, 8)

Carboplatin (AUC 2, IV, d 1, 8)

BSI-201 (5.6 mg/kg, IV, d 1, 4, 8, 11)

Gemcitabine (1000 mg/m2, IV, d 1, 8)

Carboplatin (AUC 2, IV, d 1, 8)

Gemcitabine (1000 mg/m2, IV, d 1, 8)

Carboplatin (AUC 2, IV, d 1, 8)

Gemcitabine (1000 mg/m2, IV, d 1, 8)

Carboplatin (AUC 2, IV, d 1, 8)

RESTAGINGEvery 2 Cycles

Metastatic TNBCN = 120

13

• Enrollment: October 2007 – March 2009 of 123 patients

• 74 of 116 treated patients are off study treatment as of data cutoff of March 31, 2009

• Efficacy determined by investigator assessment and RECIST criteria

• Hazard ratios estimated from Cox proportional hazards regression model

• Evaluation of 120 patients provides 80% power with one-sided alpha of 0.05 to detect an increase in CBR from 0.45 in control arm to 0.67 in investigational arm

• Final data analyses will be performed in 4Q2009

Study Enrollment and Statistical Overview

14

Patient CharacteristicsGem/Carbo BSI-201 +

Gem/Carbo

Randomized Patients, n 62 61

Age, median (range) 52 (26-80) 55 (34-76)

Race, n (%) White

African-American Asian

Missing/Unknown

48 (77.4%)12 (19.4%)0 (0.0%)2 (3.2%)

48 (78.7%) 9 (14.8%)

1 (1.6%)3 (4.9%)

ECOG PS, n (%) 0

1Missing/Unknown

43 (69.4%)15 (24.2%)4 (6.5%)

42 (68.9%)16 (26.2%)

3 (4.9%)

Metastatic Sites,* n (%) Lung

LiverBrainBone

Lymph Nodes

33 (53.2%)27 (43.5%)6 (9.7%)

22 (35.5%)37 (59.6%)

38 (62.3%)24 (39.3%)

2 (3.3%)20 (32.8%)38 (62.3%)

Prior Therapies,* n (%) Neo/Adjuvant

Metastatic: 1 prior2 prior

38 (64.4%)

13 (22.0%) 8 (13.5%)

32 (56.1%)

19 (33.3%) 6 (10.5%)

Bevacizumab Taxane Anthracycline Taxane & Anthracycline

5 (8.4%)4 (6.7%)4 (6.7%)

32 (54.2%)

7 (12.2%)12 (21.0%) 6 (10.5%)32 (56.1%)

*Includes patients dosed only (n = 59 and n = 57 for each arm, respectively) 15

PARP1 is Upregulated in TNBC

Gene expression profiling showed that PARP1 was significantly upregulated in the majority of triple negative breast cancers (n = 50)

PARP1 mRNA(Red Fluorescence Units Normalized to -Glucoronidase)

P < 0.0001

16

Preliminary Efficacy Results*

Gem/Carbo(n = 44)

BSI-201 + Gem/Carbo

(n = 42) P-value

Objective Response Rate n (%)

7 (16%) 20 (48%) 0.002

**Clinical Benefit Rate n (%) 9 (21%) 26 (62%) 0.0002

*Includes patients enrolled before September 30, 2008 and patients who had a confirmed response or disease progression

**Clinical Benefit Rate = CR + PR + SD ≥ 6 months

17

Progression-Free Survival

18

BSI-201 + Gem/Carbo (n = 57)

Median PFS = 6.9 months

Gem/Carbo (n = 59)

Median PFS = 3.3 months

P < 0.0001

HR = 0.342 (95% CI, 0.200-0.584)

Overall Survival

19

BSI-201 + Gem/Carbo (n = 57)

Median OS = 9.2 months8

Gem/Carbo (n = 59)

Median OS = 5.7 months

P = 0.0005

HR = 0.348 (95% CI, 0.189-0.649)

Safety Summary

• No differences in hematologic or non-hematologic toxicities

• No differences in gemcitabine/carboplatin dose reductions between study arms

20

Safety – Hematologic Toxicity

Gem/Carbo(n = 59)

BSI-201 + Gem/Carbo(n = 57)

Grade 2

Grade 3

Grade 4

Grade 2

Grade 3

Grade 4

Anemia, n (%)12

(20.3%)7

(11.9%)0

(0.0%)

15(26.3%

)

7

(12.3%)

0 (0.0%)

Thrombocytopenia, n

(%)7

(11.9%)6

(10.2%)

6

(10.2%)

4 (7.0%)

6

(10.5%)

7(12.3%)

Neutropenia, n (%)7

(11.9%)18

(30.5%)13

(22.0%)

7 (12.3%

)

18

(31.6%)

7(12.3%)

Febrile neutropenia, n (%)

0 (0.0%)

3 (5.1%)

1 (1.7%)

0 (0.0%)

0 (0.0%)

0 (0.0%)

RBC treatment*, n (%)5

(8.5%)5

(8.5%)2

(3.4%)3

(5.3%)5

(8.8%)2

(3.5%)

G-CSF Use, n (%)6

(10.2%)6

(10.2%)3

(5.1%)4

(7.0%)5

(8.8%)1

(1.8%)*Transfusion and/or EPO use 21

Gem/Carbo(n = 59)

BSI-201 + Gem/Carbo(n = 57)

Grade 2

Grade 3

Grade 4

Grade 2

Grade 3

Grade 4

Nausea, n (%)10

(16.9%)2

(3.4%)0

(0.0%)

7

(12.3%)

0 (0.0%)

0 (0.0%)

Vomiting, n (%)9

(15.3%)0

(0.0%)0

(0.0%)4

(7.0%)1

(1.8%)0

(0.0%)

Fatigue, n (%)10

(16.9%)6

(10.2%)0

(0.0%)10

(17.5%)1

(1.8%)0

(0.0%)

Neuropathy, n (%)

2 (3.4%)

0 (0.0%)

0 (0.0%)

1(1.8%)

0 (0.0%)

0 (0.0%)

Diarrhea, n (%)6

(10.2%)1

(1.7%)0

(0.0%)1

(1.8%)1

(1.8%)0

(0.0%)

Safety – Non-Hematologic Toxicity

22

Conclusions

• PARP1 was upregulated in most evaluated TNBC patients

• BSI-201 + gemcitabine/carboplatin was well tolerated and did not potentiate chemotherapy-related toxicities

• BSI-201 improved patients’ clinical outcomes

– Clinical Benefit Rate (62% vs. 21%; P = 0.0002)

– ORR (48% vs. 16%; P = 0.002)

– Median PFS (6.9 months vs. 3.3 months; P < 0.0001)

– Median OS (9.2 months vs. 5.7 months; P = 0.0005)

Promising safety and efficacy data from this Phase II study justify

further investigation of BSI-201 in a Phase III study

23

Phase III Metastatic TNBC StudyOpen-Label, Randomized Safety and Efficacy Trial of Gemcitabine/Carboplatin ± BSI-201 in Metastatic TNBC

• Primary Endpoints

– Overall Survival

– Progression-Free Survival

• Patients randomized to chemotherapy alone may crossover to receive BSI-201 at disease progression

• Planned Initiation: Late June 2009

• For more information: http://www.BiParSciences.com

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Acknowledgements

• Participating patients

• US Oncology investigators and research coordinators

• Karla Burgos, US Oncology Project Management

• Phase I investigators of BSI-201 who enabled this study

– Anthony Tolcher

– Elisabeth Heath

– Scott Kopetz

– Nancy Lewis

– Patricia LoRusso

– Monica Mita

– Kyri Papadopoulos

25