1. 1 Cancer Steering Committee Project Update May 2009

2. 2 Table of Contents I.Introduction II.Project Overview – I-SPY TRIAL-2: An Adaptive Breast Cancer Trial Design in the Setting of Neoadjuvant Chemotherapy

3. 3 I - Introduction

4. 4 180.7 586.8 193.9 53.3 190.1 231.5 0 100 200 300 400 500 600 Heart Diseases Cerebrovascular Diseases Cancer 1950 2003 Deaths Per 100,000 Americans Source for 2006 deaths and diagnoses: American Cancer Society (ACS) 2006 Cancer Facts & Figures; Atlanta, Georgia Source for 2003 age-adjusted death rate: National Center for Health Statistics, U.S. Department of Health and Human Services, NCHS Public-use file for 2003 deaths. Unlike Other Major Disease Killers, Cancer Continues to Take Nearly the Same Toll as It Did in 1950, ~560,000 American Deaths Annually ~ 1.4 million Americans will be diagnosed with cancer this year ~ $200 billion annually for cancer healthcare costs ~ Numbers of new cancer cases will approach 2 million by 2025 (aging of the baby boomers)

5. 5 Treatment Selection In Vitro DiagnosticsTreatment Selection In Vitro Diagnostics Treatment Selection Define Genetic Links to Disease Treatment Monitor and Prevent or Treat Early Treatment Monitoring (In Vitro Diagnostics, Imaging) targeted treatment detect monitor predict target The Biomarkers Consortium projects are a next step toward realizing the vision for 21st Century Personalized Cancer Medicine

6. 6 Target Identification and Validation Assay Development Lead Generation Lead Optimization Pre- Clinical Develop- ment Phase I Phase II Registra- tion Global Launch Global Optimization Phase III $500-600 MM $800 MM Cumulative Investment Risk Hypothesis Generation Clinical Candidate Development Commercialization $20-60 MM $200-300 MM Time – 8-12 Years The Current Drug Development Model is High Risk and Very Expensive

7. 7 Biomarkers are seen as key to reducing the time and expense required to bring new drugs to market The 2004 FDA Critical Path Initiative challenged the pharmaceutical industry to reduce the time (12-15 years) and expense (~$1-2 billion) to bring a drug to market The Oncology Biomarker Qualification Initiative (OBQI) is an FDA-NCI/NIH-CMS (Centers for Medicare & Medicaid Services) collaboration launched in 2006 to promote the development and qualification of biomarkers to accelerate drug development Cancer biomarkers are leading the way via high-profile successes such as Herceptin targeting Her2+ tumors However, despite such successes and promise, much remains to be done…

8. 8 * Polanski and Anderson (2006). A List of Candidate Cancer Biomarkers for Targeted Proteomics. Biomarker Insights 2:1– 48 Out of 1,261 putative cancer protein or peptide biomarkers described in the literature*, only 9 are FDA-approved as tumor associated antigens Fewer than 1 per year have been approved by the FDA since 1998 This high percentage of unvalidated biomarkers is generalizable to other diseases This biomarker barrier in which candidate biomarkers have not been validated needs to be overcome

9. 9 Mission: Advance the development, qualification and regulatory acceptance of biomarkers Make Consortium project results broadly available to the entire research community Six projects (~$13 million funding) launched to date Five projects ( ~$20 million total funding) in near-term pipeline The Biomarkers Consortium (BC)

10. 10 Ini tia l Id ea or Co nc ep t App rov ed Proj ect Con cep t Pro ject Pla n Ap pro ved Pro jec t La un ch EC/SC, RFA/RFP or External Submission Steering Committee/ Project Team Executive Committee (and Funders) Project Team Steering Committee Scientific merit Pre-competitive Feasibility Initial funding scan Protocol Resources Intellectual property Data sharing and distribution Timelines and milestones Budget Human subjects Privacy Legal review Final QA/QC Contracts Project management 1 2 3 4 5 BC projects undergo a comprehensive vetting and development process to advance from concept to fully planned project

11. 11 Co-Chairs: –Anna D. Barker, PhD, Deputy Director for Advanced Technologies and Strategic Partnerships, National Cancer Institute –David R. Parkinson, M.D., President and CEO, Nodality, Inc. (ex- Amgen, Biogen-Idec) Began operations in April 2007 39 members representing NIH, FDA, academia, industry and non- profit/advocacy groups Two projects currently being executed –FDG-PET Lung and Lymphoma Projects ($10.18M budget: $6.53M from 9 industry partners and $3.75M from NCI) Five additional project concepts have been approved by the CSC to date for further development A multi-stakeholder Cancer Steering Committee (CSC) identifies, develops, and oversees management of all Consortium-sponsored cancer biomarkers projects

12. 12 Cancer Steering Committee membership (1) Full NameAffiliation Aram Adourian, Ph.D.BG Medicine Inc. Binita S. Ashar, M.D., MBA, FACSU.S. Food and Drug Administration Anna D. Barker, Ph.D., co-chairNational Cancer Institute J. Carl Barrett, Ph.D.Novartis Institutes for Biomedical Research, Inc. Donald A. Berry, Ph.D.The University of Texas M.D. Anderson Cancer Center David K. Bol, Ph.D.Avalon Pharmaceuticals Bill BroKidney Cancer Association Peter F. Bross, MDU.S. Food and Drug Administration Glen Clack, M.B., MFPMAstraZeneca Pharmaceuticals Edwin Clark, Ph.D.Bristol-Myers Squibb Christina M. Coughlin, M.D., Ph.D.Wyeth Research William S. Dalton, Ph.D., M.D.H. Lee Mofitt Cancer Center & Research Institute Louis J. DeGennaro, Ph.D.The Leukemia & Lymphoma Society Chaitanya Divgi, MDUniversity of Pennsylvania James M. Doroshow, M.D.National Cancer Institute David Geho, M.D., Ph.DMerck Joe W. Gray, Ph.D.Lawrence Berkeley National Laboratory Brian G. Healey, Ph.D.EMD Serono Research Institute Andrew Hughes, MDAstraZeneca Pharmaceuticals

13. 13 Cancer Steering Committee membership (2) Full NameAffiliation Gordon F. Kapke, Ph.D.Covance Central Laboratory Services, Inc. Gary J. Kelloff, M.D.National Cancer Institute Samir Khleif, M.D.U.S. Food and Drug Administration Douglas P. Malinowski, Ph.D.TriPath Oncology Michael Meyers, Ph.D.Johnson & Johnson Pharmaceutical Research & Development Stanislaw Mikulski, M.D., FACPHoffmann-LaRoche, Inc. Gordon Mills, M.D., Ph.D.U of Texas MD Anderson Cancer Center David R. Parkinson, M.D., co-chairNodality, Inc. Uma Prabhakar, Ph.D.Centocor R&D, Inc. Richard L. Schilsky, M.D.University of Chicago Mitchell Schnall, M.D., Ph.D.University of Pennsylvania Jeffrey R. Shuster, Ph.D.Metabolon, Inc. Barry A. Siegel, M.D., Ph.D.Washington University School of Medicine Ellen V. Sigal, Ph.D.Friends of Cancer Research Christopher Slapak, M.D.Eli Lilly and Company Catherine Novotny Smith, Ph.D.Battelle Memorial Institute Dominic G. Spinella, Ph.D.Pfizer, Inc. Daniel C. Sullivan, M.D.National Cancer Institute Karen Weiss, M.D.U.S. Food and Drug Administration

14. 14 1)Establishing biomarkers to enhance cancer drug development – and diagnostics – to improve cancer patient care 2)Priority given to biomarkers addressing the requirement identified in the FDA Critical Path for robust and innovative tools for accelerating drug development 3)Trials that feature defined and measurable endpoints of response to an intervention – and the ability of the endpoint to measure/reflect clinical benefit 4)Development of predictive and prognostic biomarkers based on a fundamental understanding of cancer biology The CSC has established four focus areas for biomarker project development…

15. 15 1)Proposed target biomarkers fit biological mechanism(s) of neoplastic progression 2)Biomarker measurement is clinically feasible 3)Biomarker measurement has potential impact (incidence/prevalence of disease, mortality/morbidity, etc.) 4)Feasibility of evaluation/use 5)Feasibility of commercialization …and a panel of specific criteria for evaluating the merit of proposed project concepts*

16. 16 Number, PITitleDuration, dollars 1. Howard Scher, MSKCC Circulating Tumor Cells as Biomarkers of Castration- Resistant Metastatic Prostate Cancer: Validation into Clinical Practice 4 years $2.8 million 2. Richard Schilsky, U Chicago Detection and Characterization of Circulating Tumor Cells in Prospective Cancer Treatment Trial (CALGB Neoadjuvant Breast Cancer Trial 40601) 4 years $2.7 million 3. Richard Schilsky, U Chicago Detection and Characterization of Circulating Tumor Cells in Prospective Cancer Treatment Trial (CALGB Metastatic Breast Cancer Trial 40502) 5 years $4.9 million 4. Mitch Schnall, U Penn DCE-MRI Technique Optimization Study Using Prostate Cancer as a Model System 1.5 year $1.9 million 5. Laura Esserman, UCSF I-SPY TRIAL-2: An Adaptive Breast Cancer Trial Design in the Setting of Neoadjuvant Chemotherapy 5 years, ~$8-9 million The CSC is currently developing five projects, with a total projected cost of ~$20 million

17. 17 Number, PITitleStatus 1. ScherCirculating Tumor Cells as Biomarkers of Castration-Resistant Metastatic Prostate Cancer Project Plan fully approved in November, 2008 Target launch 3Q 2009 2. SchilskyCirculating Tumor Cells Companion Study in CALGB 40601 Neoadjuvant Breast Cancer Clinical Trial Project Plan approved April, 2009 Target launch 4Q 2009 3. SchilskyCirculating Tumor Cells Companion Study in CALGB 40502 Metastatic Breast Cancer Clinical Trial Project Plan approved April, 2009 Target launch 4Q 2009 4. SchnallDCE-MRI Technique Optimization Study Using Prostate Cancer as a Model System Project Plan fully approved in February, 2009 Target launch 3Q 2009 5. Esserman I-SPY TRIAL-2: An Adaptive Breast Cancer Trial Design in the Setting of Neoadjuvant Chemotherapy Expect Project approval June, 2009 These five CSC approved projects are in different stages of development …

18. 18 I-SPY TRIAL-2: An Adaptive Breast Cancer Trial Design in the Setting of Neoadjuvant Chemotherapy Laura Esserman, M.D., MBA 5 years, $8-9 million [In development]

19. 19 Investigation of Serial studies to PredictYourTherapeutic Response with Imaging and And moLecular analysis I SPY WITH MY LITTLE EYE....... A BIOMARKER BEGINNING WITH X.... The I-SPY 2 project under development follows and builds on the earlier I-SPY 1 trial (CALGB INTERSPORE ACRIN NCICB, CALGB 150007/150012, ACRIN 6657)

20. 20 The I-SPY 2 study proposes to introduce and rapidly test novel targeted strategies at the time of primary cancer diagnosis, rather than waiting until they develop metastatic disease Neoadjuvant therapy allows visualization of tumor response to treatment, and thus is the ideal platform to identify mechanisms of resistance, develop diagnostic markers, and individualize therapy

21. 21 I-SPY 2 is an adaptive trial design approach to identify successful treatment regimens for Stage II/II breast cancer 1.Patient presents with >3 cm invasive breast cancer (MRI imaging via Sentinelle) signs informed consent #1 [at 10-20 trial sites] for biopsy to determine eligibility 2.Core biopsy at sites to determine eligibility, samples sent to Agendia and Theranostics to measure molecular biomarkers results to Data Coordinating Center (DCC) and sites 3.Eligible patients sign informed consent #2 at sites to participate in trial 4.DCC randomizes patients adaptively to one of several new agents donated by participating pharma companies, with probability of agent assignment based on biomarker signature and data to date for that signature, + taxane, + trastuzumab if HER2+; 12 cycles, and then 4 cycles of AC (adriamycin & cyclophosphamide) are provided 5.MRI imaging, biopsy, and tissue analysis performed at intervals, used to determine pathCR and the efficacy of the new agents reported to DCC 6.Patient undergoes surgery, final tissue collection, additional biomarker analysis by Agendia and Theranostics with results reported to the DCC 7.Results used by DCC and CRO to adapt the agent assignment probabilities for each biomarker signature, so subsequent patients are better treated within the trial, and agents are graduated or dropped as soon as possible 8.Aggregated, summary data is reviewed by the BC Project Team, and made widely available via journal publications and NCI databases [Patients continue to be followed up by their treating physicians for up to 10 years, adjuvant therapy as needed]

22. 22 The I-SPY 2 Adaptive Trial design will stratify the patients into two arms based on HER2 receptor status Stratifying Biomarkers: Class I/II devices:HER2 (IHC, FISH) MammaPrint ER, PR IDE:MammaPrint44K Her2 (RPMA, 44K-microarray) Biopsy used for Biomarkers MRI Biopsy MRI Blood Surgery Biopsy Blood MRI Biopsy Tissue Paclitaxel ± New Drug C, D or E (12 Weekly Cycles) AC (4 Cycles) HER2 (+) HER2 (–) Paclitaxel+Trastuzumab ± New Drug A, B, or C Randomize On Study Randomize AC (4 Cycles) ADAPT

23. 23 The eight biomarker signatures will be used to assign participants to drug regimens. An adaptive design will improve these assignments as the trial proceeds, benefiting patients Drugs and signatures will graduate from the trial: - Based on effectiveness - Based on prevalence There are 2^8 biomarker signatures (8 bins), but this study will use only the marketable signatures (~20) Key: MP: MammaPrint High 1 or High 2 HR+: Hormone Receptor+: Either ER+ or PR+ The projected frequencies of those signatures based on I-SPY 1 findings: MP1MP2 HR+HR-HR+HR- HER2+.16.07.04.10 HER2-.23.06.28

24. 24 I-SPY 2 is an important next step toward the era of personalized medicine The adaptive trial design will allow faster decision-making about whether drugs are succeeding or failing, and thus accelerate drug development. This new model for drug testing should streamline drug development and pave the way to a better regulatory pathway The I-SPY team benefits from an existing infrastructure from I- SPY 1, fostering cross-disciplinary science involving oncology, imaging science, in vitro device development, and adaptive trial design Pre-specification of treatment assignments with different drug classes, to patients with different tumor molecular/imaging signatures, should permit simultaneous participation of multiple industry partners without concerns about conflicting economic or intellectual property interests

25. 25 The I-SPY 2 Trial will be executed over five years Site Initiation I-SPY 2 Project Implementation Study Drug Management IV III II Pre-Study Activities I Project Management Data Management Statistical Tasks Meeting Planning and Execution, Other Activities Final Report/ Manuscript/ Technical Writing Trial Ends June 2013 Trial Starts June 2009 2008200920102011201320142015 H1H2H1H2H1H2H1H2H1H2H1H2H1H2 Project Starts February 2008 Pre-study activities Protocol Development Informed Consent Investigator ID, Qualification, Recruitment Drug Selection

26. 26 There are four key operational partners with multiple roles in I-SPY 2, and multiple participating companies and sites National Cancer Institute (NCI) –Primary sponsor –Proposed manager of I-SPY 2 clinical trial CRO (CCS Associates) –Clinical research organization running the trial on behalf of the NCI The Biomarkers Consortium –Cancer Steering Committee –Managing the Project Team, and subteams –Fundraising UCSF, Lead institution (Dr. Laura Esserman, PI) –MD Anderson, Statistical Analysis Center (Dr. Don Berry, Co-PI)