OverviewI-SPY TRIAL Program

I-SPY 1 (2002-2009)I-SPY 2 (2009-2012 and beyond)

January 28, 2009

Problems with the current approach to treatment of Breast Cancer:

• Inability to predict which patients will relapse and tailor interventions for those women at high risk of recurrent breast cancer

• Need to efficiently validate and improve biomarkers for optimizing therapy

• Need to efficiently test targeted agents to determine which agents will be useful and for whom– Short term: Improve % of complete pathological responders

– Long term: Improve disease-free survival

Potential Solutions Through Novel Neoadjuvant Trials

• Opportunity to integrate biomarkers and surrogate endpoints into the process of care

• Can allow rapid assessment of targeted therapeutics with proximal endpoints of response

• Accumulate sufficient evidence about the performance of biomarkers to identify patients sensitive to these agents and document effects on targets of interest leading to larger Phase III studies

• Provide a framework to integrate data from the point of care with tools to process molecular and imaging data

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TTherapeuticherapeuticRResponse withesponse with

IImaging maging AAndnd

momoLLecularecular analysisanalysis

CALGB, INTERSPORE, ACRIN, NCICB

CALGB 150007/150012 & ACRIN 6657CALGB 150007/150012 & ACRIN 6657

I-SPY 1 Objectives• Primary

– To determine if MRI measurements of tumor response stratify patients with Stage III breast cancer into groups with statistically different disease-free survival

– To determine if MRI measurements of tumor response measured after the first cycle of neoadjuvant chemotherapy predict which patients will ultimately have a poor clinical response

• Secondary– To determine if MRI and/or molecular markers at baseline or early in

treatment predict three-year DFS– To determine if molecular markers or MRI are better than residual

disease in predicting outcome– To determine if molecular markers are associated with specific MRI

patterns– To determine if molecular markers at baseline predict MRI

changes/response

Surgery

& RT

Anthracycline Taxane

Tam if ER+

I-SPY 1 Clinical Trial Backbone

Serial MRI Scans (longest diameter, tumor volume, tumor morphology)& Serial Core Biopsies

Layered Imaging/Molecular Biomarker Studies onto Standard Clinical Care of Women with Measurable Disease (≥3cm)

I-SPY 1 Biomarker Platforms

Expression Arrays

)

-2

-1

0

1

2

3

4

5

Genome location

relative copy

num

ber (Lo

g2)

1 3 5 7 9 11 13 15 17 19 21 X

1q 20q

1p 17p 19p

CGH

Reverse Phase Tissue Protein Lysate Arrays

Tissue: Core or Surgical

H&E,IHC,FISH

UNC, Penn UNC, UCSF George Mason

UCSF

Id1 proteinsautoantibodies

phosphoproteins

Serum

Specimen Collection and Processing

• Specific SOPs for frozen and paraffin tissue (over 3,000 specimens collected)

• Close collaboration between pathologists and radiologists

• Study pathologist evaluates using residual cancer burden (RCB), pCR (Symmans, JCO 2007)

Total Accrual: 237 Institution Name Accrual

University of Pennsylvania Medical Center 36 Georgetown University Hospital 4 University of North Carolina 36 Memorial Sloan Kettering Cancer Center 22 University of Washington 5 University of Alabama at Birmingham Medical Center

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University of Chicago 2 University of Texas Southwestern 14 University of California San Francisco 67

Gene Expression, Tissue Arrays, Imaging, H&E

Images

Specimens, IHC, FISH Assays

Protocols, Accruals

Clinical Case Report Forms, Patient Demographics

Analysis Tools

I-SPY TRIAL Web Portal

I-SPY Data Portal – Hosted at NCICB

What have we learned from I-SPY 1? pCR by Biomarkers

*Excluding Patients who received Herceptin (n=16)

pathologic Complete Response

ER+ ER-HER2+ 28.1% 48.1% 37.3%HER2- 9.6% 35.7% 18.4%

14.8% 40.6% 24.5%

pCR: pCR: 27% 27% (56/210)(56/210)

no pCR: 73% no pCR: 73% (154/210)(154/210)

Predictor P ValueNKI 70 genes (Van ‘t Veer) 0.007GHI Recurrence Score (Paik) 0.007T-FAC 30 gene set (MDACC) 0.02TP53 (Perou) 0.01Molecular Subtypes (Sorlie) 0.02ER, Phospho ER (-) 0.0002Her-2, Phospho Her-2 0.009MRI Volume significant

Molecular Predictors of pathologic Complete Response (pCR)

Data Sharing and Oversight

• Development of Data Sharing Agreement• I-SPY Publications and Steering Committees • Authorship guidelines• All investigators granted access to data for

purposes of analysis– broad access to data based on review of concept

sheet by I-SPY Steering Committee

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I-SPY 1• Evaluated biomarkers and imaging for predicting

response to standard neoadjuvant chemotherapy

I-SPY 2

• Evaluate Phase II drugs in combination withstandard chemotherapy in a neoadjuvant setting

• Use biomarkers to stratify patients based ontheir predicted likelihood of response to treatment

• Use imaging to measure response

I-SPY 2 TRIAL Sponsors:NCI, FDA, NCICB, NIH Foundation

Critical Path Initiative

1616

Accrual: Anticipate 800 patients over 3–4 years

Enrollment: ~20 patients per month

No. of Sites: 15–20 across US and possibly Canada

On Study

MRI MRIBiopsy

MRIBlood

Surgery

BiopsyBlood

MRI Biopsy

Tissue

Taxane +/– New Drug(12 weekly cycles)

AC (4 cycles)

I-SPY 2 Adaptive Trial General OutlinePhase 2 Neoadjuvant

I-SPY 2 Adaptive Trial General OutlinePhase 2 Neoadjuvant

Patient presents with ≥3cm invasive cancer

II--SPY 2 Adaptive Trial Schema:SPY 2 Adaptive Trial Schema:Screening & RandomizationScreening & Randomization

Pt is On Study

Core biopsy to assess eligibility

Eligibility determined by:• ER, PR• HER 2 (IHC/FISH, Gene Expression, Protein Microarray)• MammaPrint score (from full 44k microarray)

Patient randomized to treatment arm on basis of:• ER, PR status• HER 2 status• MammaPrint score

Patients who are MammaPrint Low, ER Positive, and HER 2 Negative, will not be eligible for I-SPY 2, as they would not be considered ideal candidates for chemotherapy

Pt NOT On Study

18

Taxane + Herceptin +

New Agent A

Taxane + New Agent C

Pt is On Study

Taxane + Herceptin

Taxane + Herceptin +

New Agent B

Taxane + Herceptin +

New Agent C

Taxane

Taxane + New Agent D

Taxane + New Agent E

AC

ACHER 2 (+)

HER 2(–)

Randomized

Randomized

Surgery

Surgery

II--SPY 2 Adaptive Trial Schema:SPY 2 Adaptive Trial Schema:Patient on Treatment, Serial MRI to Assess ResponsePatient on Treatment, Serial MRI to Assess Response

19

Taxane + Herceptin +

New Agent A

Taxane + New Agent C

Pt is On Study

Taxane + Herceptin

Taxane + Herceptin +

New Agent B

Taxane + Herceptin +

New Agent C

Taxane

Taxane + New Agent D

Taxane + New Agent E

AC

ACHER 2 (+)

HER 2(–)

Randomized

Randomized

Surgery

Surgery

II--SPY 2 Adaptive Trial Schema:SPY 2 Adaptive Trial Schema:Randomization is Dependent on How Previous Patients Responded toRandomization is Dependent on How Previous Patients Responded to a Treatmenta Treatment

Learn, Adapt from Learn, Adapt from each patient as we each patient as we

go alonggo along

I-SPY 2: Adaptive Phase IINeoadjuvant Breast Cancer Trial

Design• Eligibility: Moderate to high-risk breast cancer

• Primary endpoint: pCR

• Accrual: Anticipate 800 patients over a 3-4 years

• Evaluate many drugs & combinations in parallel in randomized Phase II study branches

– Successes graduate to Phase III– Underperformers dropped for futility

• Study branch assignment based upon baseline biopsy biomarker assessment and response of prior patients

Proposed Agents• Tier 1 agents being considered (ready Fall 2009)

– IGFR inhibitors– Combination MTOR plus anti-angiogenesis drugs – Her2 targeted agents– Death Pathway agents (Apo/TRAIL combination)– cMET inhibitors– Multikinase inhibitors

• Tier 2 agents (ready within 1 year of study activation)– PI3kinase– Hedgehog– Notch– AKT inhibitors– Combinations with MEK and others

• Multiple agents within class will NOT be tested

Biomarker Categories• Biomarkers for stratification are required to have FDA approval

– IHC and FISH for ER, PR, and Her2– MammaPrint – Additional markers in FDA IDE approval process

• pHer2 & Her2 by RPMA, mRNA Her2 by 44k microarray• MRI volume

• Qualifying Biomarker Definition– Performed under CLIA conditions within the I-SPY 2 TRIAL– Shows promise for predicting response to standard agents or

novel therapies

• Exploratory Biomarker Definition– Reflect next generation technology– Purpose is to enable trial to evolve and keep pace with

technology

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Biomarker ExamplesQualifying Biomarkers• Panomics assay for drug and prognostic predictors• RPMA pathway markers for stratification and prediction of response• RCB predictor of response

Exploratory Biomarkers:• DNA methylation• Exon capture sequencing • RPMA pathway discovery and profiling• Copy number and SNP chip• Pharmacogenomics (germline SNP)• miRNA• Panomics – 2nd generation predictors• Circulating tumor cells• MRI SER segmentation• Other drug specific markers

Timeline

First patient on-studyFall 09

Site IRB approval, budgets, contracts finalized

Apr – Aug 09

Contracts finalizedMar – Jun 09

Protocol finalizedFeb 09

Sites selection (15-20 sites)Jan – Apr 09

Agents finalizedDec 08 – Feb 09

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I-SPY 2 is a Paradigm Shift• Adaptive design allows efficient learning for

changing/adding new agents over the courseof the trial

• Uses biomarkers, imaging and pathologyendpoints to drive change

• Validates, tests, and qualifies biomarkers aswe test new agents

• Provides foundation of evidence for tailoring therapy

• Uses a collaborative multi-disciplinary teamapproach