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  • Overview I-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

  • IInvestigation ofnvestigation of SSerial studies toerial studies to PPredictredict YYourour

    TTherapeuticherapeutic RResponse 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

    re la tiv e co py

    n um

    be r ( 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 proteins autoantibodies

    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

    51

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

  • 14

    I-SPY 1 • Evaluated biomarkers and imaging for predicting

    response to standard neoadjuvant chemotherapy

    I-SPY 2

    • Evaluate Phase II drugs in combination with standard chemotherapy in a neoadjuvant setting

    • Use biomarkers to stratify patients based on their 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 MRI Biopsy

    MRI Blood

    Surgery

    Biopsy Blood

    MRI Biopsy

    Tissue

    Taxane +/– New Drug (12 weekly cycles)

    AC (4 cycles)

    I-SPY 2 Adaptive Trial General Outline Phase 2 Neoadjuvant

    I-SPY 2 Adaptive Trial General Outline Phase 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 II Neoadjuvant 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 stratific