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Cancer Steering CommitteeProject Update

May 2009

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Table of Contents

I. IntroductionII. Project Overview – I-SPY TRIAL-2:

An Adaptive Breast Cancer Trial Design in the Setting of Neoadjuvant Chemotherapy

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I - Introduction

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180.7

586.8

193.9

53.3

190.1231.5

0

100

200

300

400

500

600

HeartDiseases

CerebrovascularDiseases

Cancer

1950

2003

Dea

ths

Per

10

0,0

00

Am

eric

ans

Source for 2006 deaths and diagnoses: American Cancer Society (ACS) 2006 Cancer Facts & Figures; Atlanta, GeorgiaSource 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)

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Treatment SelectionIn 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

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Target

Identification

and Validation

↓

Assay

Development

↓

Lead

Generation

LeadOptimization

Pre-Clinical

Develop-ment

Phase I

Phase II

Registra-

tion

Global Launch

Global Optimization

Phase III

$500-600 MM

$800 MM

Cumulative Investment

Risk

HypothesisGeneration

ClinicalCandidate Development

Commercialization

$20-60 MM

$200-300 MM

Time – 8-12 Years

The Current Drug Development Model isHigh Risk and Very Expensive

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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…

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* 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

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• 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)

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Initial

Idea or Concept

Approved

Project Concep

t

ProjectPlan

Approved Project

Launch

EC/SC,RFA/RFP or

ExternalSubmission

SteeringCommittee/

ProjectTeam

ExecutiveCommittee

(and Funders)Project Team

SteeringCommittee

• 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

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• 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

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Cancer Steering Committee membership (1)

Full Name Affiliation

Aram Adourian, Ph.D. BG Medicine Inc.

Binita S. Ashar, M.D., MBA, FACS U.S. Food and Drug Administration

Anna D. Barker, Ph.D., co-chair National 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 Bro Kidney Cancer Association

Peter F. Bross, MD U.S. Food and Drug Administration

Glen Clack, M.B., MFPM AstraZeneca 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, MD University of Pennsylvania

James M. Doroshow, M.D. National Cancer Institute

David Geho, M.D., Ph.D Merck

Joe W. Gray, Ph.D. Lawrence Berkeley National Laboratory

Brian G. Healey, Ph.D. EMD Serono Research Institute

Andrew Hughes, MD AstraZeneca Pharmaceuticals

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Cancer Steering Committee membership (2)

Full Name Affiliation

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., FACP Hoffmann-LaRoche, Inc.

Gordon Mills, M.D., Ph.D. U of Texas MD Anderson Cancer Center

David R. Parkinson, M.D., co-chair Nodality, 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

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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…

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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*

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Number, PI

Title Duration, 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

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Number, PI

Title Status

1. Scher Circulating Tumor Cells as Biomarkers of Castration-Resistant Metastatic Prostate Cancer

Project Plan fully approved in November, 2008Target launch 3Q 2009

2. Schilsky Circulating Tumor Cells Companion Study in CALGB 40601 Neoadjuvant Breast Cancer Clinical Trial

Project Plan approved April, 2009 Target launch 4Q 2009

3. Schilsky Circulating Tumor Cells Companion Study in CALGB 40502 Metastatic Breast Cancer Clinical Trial

Project Plan approved April, 2009Target launch 4Q 2009

4. Schnall DCE-MRI Technique Optimization Study Using Prostate Cancer as a Model System

Project Plan fully approved in February, 2009Target 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 arein different stages of development…

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I-SPY TRIAL-2: An Adaptive Breast Cancer Trial Design in the

Setting of Neoadjuvant Chemotherapy

Laura Esserman, M.D., MBA5 years, $8-9 million

[In development]

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Investigation ofSerial studies toPredictYourTherapeuticResponse withImaging andAndmoLecular 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)

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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

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I-SPY 2 is an adaptive trial design approach to identify successful treatment regimens for

Stage II/II breast cancer1. 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]

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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, PRIDE:MammaPrint44K

Her2 (RPMA, 44K-microarray)

Biopsyused for

Biomarkers

MRI MRIBiopsy

MRIBlood

Surgery

BiopsyBlood

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

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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 2HR+: Hormone Receptor+: Either ER+ or PR+

The projected frequencies of those signatures based on I-SPY 1 findings:

MP1 MP2HR+ HR- HR+ HR-

HER2+ .16

.07

.04

.10

HER2- .23

.06

.06

.28

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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

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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 ManagementStatistical Tasks

Meeting Planning and Execution, Other Activities

Final Report/Manuscript/Technical Writing

Trial EndsJune 2013

Trial StartsJune 2009

2008 2009 2010 2011 2013 2014 2015H1 H2 H1 H2 H1 H2 H1 H2 H1 H2 H1 H2 H1 H2

Project StartsFebruary 2008

Pre-study activities• Protocol Development• Informed Consent• Investigator ID,

Qualification, Recruitment

• Drug Selection

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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)