The NeoBIG program

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Pre-IMPAKT Training
Course , May 6th 2009, Brussels
The NeoBIG program
Research program to accelerate drug biomarker
development in early breast cancer 2009 - 2014
Phuong Dinh, MD Breast International Group (BIG
aisbl)
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Rationale for NeoBIG
Long, complex and resource intensive ? 400-900
million ? gt10 years
High attrition rate in the later phases ? 6
to marketing

Drug Development Process
Many Bottlenecks
For Patients Delayed access and more expensive
therapies
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Rationale for NeoBIG

POSSIBLE REASONS FOR THE INEFFICIENT DRUG
DEVELOPMENT PROCESS
1. Ineffective Drugs
2. Unselected patient populations
3. Outdated trial designs
4. Lack of predictive and prognostic biomarkers
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New model of early BC trials
Each trial will assume two strategies Strategy
A Standard of care Strategy B New and
potentially superior strategy There are three
hypotheses associated with each trial Hypothesis
1 Benefit of 1 surrogate endpoint in B vs A in
neoadjuvant setting Hypothesis 2
Molecular markers profile triggering this
benefit Hypothesis 3 Clinical benefit of B over
A in early breast cancer

Neo-adjuvant population N
300-500
Hypothesis 1 Secured ? No / Yes
TEST Hypotheses 12 Perform gene /
protein profiling
Refine Hypothesis 2
Frozen tissue / TMAs Molecular Imaging CTC
Continue
Adjuvant population N2000-5000 (Registration
trial)
VALIDATE Hypothesis 2 (Statistical
considerations, pt selection criteria
revisited) VALIDATE Hypothesis 3 or REFINE
DESIGN of Pivotal Trial
Tissue microarrays
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Overall NeoBIG Schema
Targeted neo-adjuvant trials involving targeted
agents
Neoadjuvanttrial 1
Luminal non-A
SURGERY
Neoadjuvanttrial 2
Basal-like
HORIZONTAL
Neoadjuvanttrial 3
BRCA-ness
Neoadjuvanttrial 4
HER-2
V E R T I C A L
PI3kinase mutation
Neoadjuvanttrial 5
Neoadjuvanttrial 6
P53 mutation
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Post NeoBIG
Promising NeoBIG drugs to be validated
Drug 3
Drug 1
Drug 5
Traditional adjuvant trials

• Greater chance of success, due to strong
  biological hypothesis
• Can validate promising biomarkers

Possibility to test stem cell-like therapies
for post-neoadjuvant residual disease e.g.
residual CTCs
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Challenge No 1 ?
COLLABORATION!!
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Proposed Structure
Central Coordination Support BIG Headquarters
Additional recruiting centres
Neo-adjuvant trials
Post-NeoBIG Traditional Adjuvant Clinical
Trials
Neo 1
Neo 2
Neo 3
NeoBIG Core Institutions (20)
Neo 4
Neo 5
Neo 6
Co 1
Co 2
Co 3
Co 6
Co 5
Co 4
Pharma Partners
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NeoBIG platform

• Core Institutions- leading academic centres
  with neoadjuvant expertise
• Multi-partner collaboration Consortium members
  pharmaceutical, imaging and bio-diagnostic
  companies
• Data-sharing access to data on control arms
  for consortium partners
• Tissue bio-banking an investment into future
  translational research
• Harmonization of procedures technical, legal,
  contractual

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Building a strong platform
Bio-specimen
Core Institutions
Ethical
Scientific
Data sharing
Legal
Financial
Imaging
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Challenge No 2 ?
Multi-disciplinary dialogue !
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The Old Cycle
Physician
Imagist
Radiotherapist
Surgeon
Oncologist
Pathologist
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The New Approach
Physician
Radiation oncologist
Imagist
Medical oncologist
Surgeon
Pathologist
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The New Approach
Novel trial designs
Targeted patient populations
New targeted drugs
Each NeoBIG trial
Functional imaging
Cutting edge translational research
Central pathology review
Surrogate endpoints
Genetics
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Each Neoadjuvant Patient

• Global NeoBIG IC
• 2 frozen biopsies
• 2 fixed biopsies
• blood sample

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Pre-randomisation Testing

Extraction of DNARNA
Transport Co
Expert SME
Academic lab
Gene signature
Gene expression profiling
Randomisation centre
Store DNA and RNA from primary tumor biopsy for
short period
Trial allocation
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Trial Allocation
NeoBIG 1
Central Pathology review results GEP results
NeoBIG 2
NeoBIG 3
NeoBIG 4
NeoBIG 5
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NeoBIG TRIAL IN LUMINAL BC
Target population
S U R G E R Y
Standard Rx
2/3 pathway activated 1/3 pathway quiescent
Investigators Choice of further
adjuvant therapy
Standard Rx Pathway Inhibitor
Tumour Biopsy
Tumour Biopsy
Path report
Ki67
Ki67
Ki67
Blood / Imaging
Blood / Imaging
Blood / Imaging
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Opportunities

• Crossing many boundaries
• Geography ? international collaboration
• Bench vs bedside ? uniting clinical and basic
  scientists
• Disciplines ? cross-fertilization between
  experts

A platform to promote YOUNG investigators
world-wide