Introduction Updates Advocate Involvement Preview of Patient Support I-SPY 2 Summary Introduction to BreastCancerTrials.org

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2 Introduction Updates Advocate Involvement Preview of Patient Support I-SPY 2 Summary Introduction to BreastCancerTrials.org 2

3 I-SPY 2 TRIAL: Key Players Multi-Sector Science Focus Group Independent Agent Selection Committee Data Access and Publication Committee (DAPC) Chair: Laura Esserman DSMB Chair: Cliff Hudis FNIH Biomarkers Consortium Executive Committee Cancer Steering Committee (CSC) Chairs: Ann Barker, David Parkinson I-SPY 2 Project Team Chair: Gary Kelloff Principal Investigators Laura Esserman, Don Berry Project Management Donya Bagheri, Meredith Buxton FNIH I-SPY 2 CRO CCS Associates, Inc. Trial Operations Group Chair: Angie DeMichele Advocates Chair: Jane Perlmutter Imaging Chair: Nola Hylton Agents Screening Chair: Doug Yee Informatics Chair: Michael Hogarth Working Groups Pathology Chair: Fraser Symmans Biomarkers Chair: Laura van t Veer Site Preparation Chair: Angie DeMichele DCC Chair: Don Berry Statistical Core Chair: Don Berry DCC CCS Associates, Inc. Sites 1,2,3 20 Sites 1,2,3 10 Sites 1,2,3 10 3

4 Primary Goal I-SPY1 Identify the best MRI and molecular markers of early response to systemic treatment for breast cancer. I-SPY2 Rapidly identify promising new agents and the patients who are most likely to benefit from them. Sponsors CALGB, ACRIN, InterSPORE FNIH, Biomarker Consortium, ACRIN Trial Design Patient Population Primary Endpoint Start/End Date Neo-adjuvant, single-arm design (non-treatment trial) ~300 Stage III breast cancer patients 3-year disease free survival following surgery Randomized, adaptive, neoadjuvant design (Phase II treatment trial) ~ 800 breast cancer patients at high risk of recurrence Pathological complete response (pcr) at time of surgery

5 Design Component P atients I nvestigational Intervention C ontrol O utcome I-SPY 2 Patients with locally advanced breast cancer Breast Cancer patients at high risk of recurrence Investigational agents that have adequate safety data when paired with Paclitaxel Taxane (12 weekly cycles), with Trastuzumab if HER2+ Followed by Anthracycline (4 cycles) Followed by surgery Tissue and blood collected throughout treatment Serial MRIs throughout treatment Primary: pathological complete response (pcr) Secondary: RFS, MRIs, biomarkers 5

6 CONSENT 1 Core biopsy to assess eligibility No Is patient: MammaPrint Low ER Positive HER2 Negative? CONSENT 2 Patient On Study Randomized to treatment arm based on: ER, PR status HER2 Status MammaPrint score Patient presents with newly diagnosed 2.5cm invasive tumor Eligibility determined by: Ability to tolerate MRI Ability to generate 44k Agilent microarray Yes Patient not on study Not considered good candidate for chemotherapy 6

7 Adapt Chemotherapy 1 +/- Investigational Drug(s) (12 weeks) Chemotherapy 2 (8-12 weeks) Screening Assign Treatment Surgery MRI Core Biopsy Blood Draw MRI Core Biopsy Blood Draw MRI Blood Draw MRI Blood Draw Tissue Accrual: 800 patients over 4 years ~20 patients per month from across sites Primary End Point: pathological Complete Response (pcr) 7

8 Unique partnerships involving all stakeholders Innovative process to assess new agents Innovative process to learn about biomarkers Innovative engagement of advocates early and often 8

9 Sponsored by Biomarkers Consortium of FNIH, a public-private partnership Responsibility shared between CCSA and UCSF Early involvement with FDA Early involvement of advocates Inclusion of multiple investigational agents from multiple manufacturers 9

10 Agents Investigational agents will leave the trial as their treatment value is established Biomarkers Patients will be assigned to investigational agents based on classifying biomarkers Predictive value of MRI volume change during treatment will be modeled Next generation biomarkers will be assessed 10

11 Introduction Updates Biomarkers Investigational drugs Trial Sites Advocate Involvement Preview of Patient Support I-SPY 2 Summary Introduction to BreastCancerTrials.org 11

12 Type Used in I-SPY 2 Status Classifier Qualification Exploratory Will be used to stratify patients and assign investigational agents Will be assessed for future use as an I-SPY 2 classifier Performed under CLIA conditions Will be studied for potential future validation Currently widely used and/or FDA qualified Strong existing evidence of potential value I-SPY 2 data may be used for FDA qualification Preliminary evidence of potential value 12

13 Type Classifier Qualification Exploratory Examples IHC for ER, PR, HER2 and FISH for HER2 MammaPrint TargetPrint HER2 by 44K microarray MRI volume Panomics assay RPMA pathway markers, pher2 RCB predictor of response DNA methylation Exon capture sequencing RPMA pathway Copy number and SNP chip Pharmacogenomics (germline SNP) mirna Panomics 2nd generation predictors Circulating tumor cells MRI SER segmentation Other drug specific markers 13

14 65 Pipeline Agents Identified 16 Agent Classes 8 Pathways Grouped Prioritized Selected Prioritize by pathways with scientific rational Only include agents with adequate safety date Independent External Advisory Committee selects one agent per class ~10 Investigational Agents will be tested in I-SPY 2 14

15 Fall 2008 Pharmaceutical Company Focus Group Produced broad list of candidate tier 1 and tier 2 agents Spring 2009 I-SPY 2 Internal Agent Review of Proposed Tier 1 Agents Produced narrowed down list of tier 1 agents plus agents deferred to tier 2 Spring 2009 I-SPY 2 Independent Agent Review of Proposed Tier 1 Agents Produces approved list of tier 1 agents Agents not included in tier 1 will be reviewed quarterly for addition to the trial pipeline 15

16 Phase I testing completed Compatible with standard paclitaxel therapy (i.e. no unacceptable additive toxicity) For HER2 agents, compatible with paclitaxel plus trastuzumab therapy Known efficacy or rationale for efficacy in breast cancer Fits strategic model for optimizing combinations of single/multiple molecular targeting drugs with or without standard chemotherapy Targets key pathways/molecules in breast cancer: Receptors PI3K Pathways MAPK Pathways Angiogenesis DNA Repair HER2, IGF1R, Death Receptor, cmet, VEGFR (multi-targeted TKI) PI3K, Akt, mtor MEK, MAPK AMG 386 PARP Note: Only one novel agent per target pathway will be active in the trial. The goal is to test agents by class. Willingness of pharmaceutical company to support the trial and sufficient availability of the agent #1 Criteria Safety with paclitaxel is known and acceptable 16 16

17 Agent PARP Inhibitor IGFR inhibitor HER2+ / Any HR Cancers HER2- / HR+ Cancers HER2 - / HR - Cancers No No Yes No Yes Yes HER2 TKI Inhibitor Yes No No APO/TRAIL No Yes Yes Vascular disrupting agent No Yes Yes 17

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19 Introduction Updates Advocate Involvement Preview of Patient Support I-SPY 2 Summary Introduction to BreastCancerTrials.org 19

20 Advocates involved in earliest thinking and planning of I-SPY 2 Advocates assigned to all I-SPY 2 scientific working groups and advisory groups Presentations to advocates at scientific meetings and advocacy meetings (e.g., AACR, SABCS, ASCO, NBCC, SHARE, C3) Regular updates to mailing list of over 120 subscribing advocates Multiple advocate driven project groups I-SPY 2 20

21 Advocate Specific Projects Patient Materials & Support Recruiting Brochure Patient Website & DVD Network of Strength Partnership Training Advocate Webinars Peer Support Counselors Informed Consenters Trial Site Support Recruitment & Retention Plan Local Web Page Local Advocates (if interest from site) Advocate Program Assessment Protocol Review Especially Informed Consent Advocate Working Groups Dissemination I-SPY 2 Info to Public Advocacy Best Practices 21

22 Introduction Updates Advocate Involvement Preview of Patient Support Patient Brochure, Website, and DVD Breast Cancer Network of Strength Partnership I-SPY 2 Summary Introduction to BreastCancerTrials.org 22

23 To increase awareness of I-SPY 2 and support the timely accrual of a diverse patient population To assist patients in making informed decisions about enrolling in I-SPY 2 (not to pressure them) To support patients who enroll in I-SPY 2 and ensure compliance to study procedures 23

24 Optional Peer Support Call Make Patients Aware of Trial Interest? No Yes Screening Consent Discussion Agree? Yes Eligible? No Yes I-SPY 2 Brochure Done I-SPY 2 Patient Website Decline Questionnaire Non-Eligibility Discussion 24

25 Yes Eligible? No Yes Randomize Treatment Consent Discussion Agree? No Yes Non-Eligibility Discussion I-SPY 2 Patient Website & DVD Decline Questionnaire 25

26 Peer Support Call (s) Exit Interview Yes Randomize Treatment Consent Discussion Agree? No Yes Enroll & Start Treatment Still on Dropped Trial Out Done? Yes I-SPY 2 Patient Website & DVD Decline Questionnaire Welcome Letter Congratutions Letter 26

27 USCF Team (Sarah and Julia) crafted a patient brochure and website content They received a great deal of input from a >20 advocates Material has been submitted to UCSF IRB; they have some concerns that are being discussed Once we agree on final text, material will be: Presented to graphic designer, web developer for a prototype Advocates will have an additional opportunity to review Material will be produced and distributed and website will go live 27

28 Safeway Foundation, a major funder of I-SPY 2 offered to developed a patient DVD Footage was shot at UCSF in October, including investigators, an advocate, and I-SPY 1 patients A draft script has been submitted to UCSF IRB When a final script is agreed upon the DVD will be completed, distributed to prospective patients, and available on the Patient Website

29 Goals: Provide potential participants in I-SPY 2 with an opportunity to discuss their diagnosis and possible clinical trial participation with trained peer counselors Provide I-SPY 2 participants with an opportunity to discuss their diagnosis and treatment issues with trained peer counselors: Encourage I-SPY 2 participants to comply with trial requirements and raise concerns with their health care provider Status: Under discussion with UCSF IRB Training for peer counselors planned for January 29

30 Introduction Updates Advocate Involvement Preview of Patient Support I-SPY 2 Summary Introduction to BreastCancerTrials.org 30

31 Design Trials with the Future in Mind Principle Test agents where they matter most Rapidly learn to tailor agents Optimize phase III trials Drive Organizational Efficiency Use Team Approach Solution Neoadjuvant setting, poor prognosis cancers Integrate advocates into trial planning Adaptive Design Neoadjuvant therapy Integration of biomarkers. imaging Graduate drugs with predicted probability of success in phase III trials for given biomarker profile Adaptive Design Master IND Test drugs by class, across many companies Shared cost of profiling Financial support separated from drug supply Shared IT Infrastructure, cabig Democratize access to data Share credit and opportunity Collaborative process for development 31

32 February 2009 Site selection 10 sites on board; Additional recruiting on-going (14 sites as of August 2009) July 2009 Agents finalized Tier 1 agents identified August 2009 Protocol finalized IRB review workshop August 20, 2009 September 4, 2009 IND application submission Response within 30 days November 2009 Sept-Dec 2009 January 2009 December/2009 January 2010 IRB approval Contract negotiations Site/Investigator training First patient on-study Begin IRB approval process at 3 sites (UCSF, U Penn, UMN). Ongoing through June 2010 Initiated with 3 site (UCSF, U Penn, UMN); Ongoing Open at UCSF, UPenn, UMN first, additional sites on-study ongoing through first quarter

33 Site FNIH Biomarkers Consortium I-SPY 1 Website I-SPY 2 Advocate Website I-SPY 2 Public Site & Patient Site Breast Cancer Network of Strength Breast Cancer Trails URL

34 Introduction Updates Advocate Involvement Preview of Patient Support I-SPY 2 Summary Introduction to BreastCancerTrials.org 34