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Prof. Jean-Marc Nabholtz, MD, MSc
Chairman
Breast Cancer
Worldwide (2000):
 > 800,000 new cases
 350,000 deaths
 Death rates:
 From 1930 until 1990: stable
 1990’s: slight decrease
Screening
Adjuvant therapy, real but Modest
Cancer Therapy Development
NEW
SINGLE
AGENT
Addition to
Prior standard
ADJUVANT
MBC
Nabholtz, May, 2001
BREAST CANCER
New Drug Development
Number factor:
 Exponential increase of number of new drugs
1970s and 80s:
1990s:
2000s:
one digit number
two digit number
explosion of biotech development
 Relatively fixed number of patients and clinical
researchers available for clinical research
BREAST CANCER
New Drug Development
 Time factor:
 Long lead time between Phase I and Adjuvant
Phase III: 20 years for doxorubicin
 Classical groups
Activation time: 18 months average
Accrual time: 2 to 5 years
Follow-up time
– Preliminary results at 3 years
– Final results at 5 to 10 years.
BREAST CANCER
New Drug Development
Key factors for the future
Patient Access
Quality of Concepts/Speed
Quality of Data
BREAST CANCER
New Drug Development
Need to adapt to the challenge:
 Quality: Academic control with global strategies
of development
 Speed:
 Globalization of processes: Worldwide network of
investigators
 Adaptation to the needs (Virtual):
 Access to patients where they are
 Use of modern means of communication
Breast Cancer New Drug Development
Academic Global Virtual Concept
BCIRG
First Academic Global Virtual
Intergroup
BCIRG PRIORITY MANDATES
 Patients
 Safety
 Improving care
 Science
 Studies of new Drugs
Vehicule: Global Strategy of Development
 Rationales built from evidence
 Scientific Independence
 Academic Collaboration
BCIRG Investigators
BCIRG Offices
Edmonton
Los Angeles
Paris
BCIRG Support
Investigators
The Academic Group:
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Group Development
New Therapy Identification
Global Strategy Development
Academic Stimulation
Statistics
Communications
Academic support
The Operations Group:
State of the Art
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CRAs and Management
Data Entry and Management
Regulatory/Safety
Trial Implementation
Information Technology
Administration
BCIRG Investigator Organization
Study
Chairs
Core Centers
Investigators
Leaders of the studies
Dedicated to BCIRG studies,
launch all phases of studies
1500 investigators from
850 centers comprise
our cooperative group
BCIRG Investigator Organization
BCIRG
…
= participating center
= participating regional/national cooperative group
= non-participating centers or group
BCIRG Scientific Advisory Board
Overall Scientific Advisory Board
Evaluation of New Compounds
Choice
Steering committees:
Hormonotherapy, Biologic modifiers, Chemotherapy
Global Strategy of Development
BCIRG Strategy Implementation
Global Strategy of Development
Advisory Board Review
BCIRG Academic Team
BCIRG Operations Team
Implementation: Phases I to III
Development of Chemotherapy
Breast Cancer
1970s
 Before anthracyclines
 CMF, CMFVP
 With anthracyclines
1980s
1990s
2000s
 Combinations: AC, FAC, AVCMF, FEC, CEF
 Sequence and Alternating (Milan A & B)
 Dose intensity,dose density, HDCT
 Taxanes (Paclitaxel/Docetaxel)
 Sequential: A T C or AC T
 Combinations: TA, TAC
 Biologic Modifiers (Herceptin)
 Integration in chemotherapy strategies
BCIRG: Genesis and Proof of Concept
 Development of Taxanes
 Taxol with BMS: Registration trial 1993-1996
 Taxotere with RPR/Aventis
7 Pivotal Phase III trials
MBC
– Tax 304: Txt vs. MV (registration trial)
– Tax 306: AT vs. AC (registration trial)
– Tax 307: TAC vs. FAC (registration support)
Adjuvant
– BCIRG 001/Tax 316: TAC vs. FAC (registration trial)
– BCIRG 002/Tax 321: TAC vs. TAC & HDCT
– BCIRG 005: ACT vs. TAC
– BCIRG 006: ACT vs. ACTH vs. TCH
Hormonetherapy
 Arimedex: Registration trial vs Tamoxifen 1st
line Metastatic with AstraZeneca
 SCH 57050 vs anastrazole metastatic breast
cancer relapsing
 Pivotal registration trial
 Complete
Development of MPO with
Searle/Monsanto
 Concept:
Improve AT/TAC toxicity profile
(Febrile Neutropenia)
 Phase III
MPO vs G-CSF after TAC
chemotherapy
(Registration Trial)
BCIRG: Current Focus (I)
2nd Generation Adjuvant Development of Taxotere/
1st Generation Adjuvant Development of Herceptin
 Adjuvant
 BCIRG 005: ACT vs. TAC
 BCIRG 006: ACT vs. ACTH vs. TCH
 Metastatic
 Phase II Pilots of TCH (BCIRG 101/102)
 BCIRG 007: TH vs. TCH (Roche Genentech)
BCIRG: Current Focus (II)
 Development of Other promising new agents :
 new biologic modifiers :
 EGFR-TKI Inhibitors (Iressa-AstraZeneca,
OSI-774-Genentech…) Iressa Global strategy
of development
Anti-Angiogenic Molecules…
 Chemotherapy (Xeloda): Registration trial of
Xeloda in adjuvant setting
 Under discussion
 Node negative High Risk
 Elderly
Evolution
 BCIRG is the Breast Cancer division of CIRG
(Cancer International Research Group)
 Present evaluation of potential other divisions
 Disease sites eg. LCIRG, GICIRG…
 Mechanistic groups: Kinase Inhibitors IRG
…others?...
 Integration of activities in Global Translational
Processes.
 with UCLA/JCCC and other Universities
 Development of Translational Tools (Cancer
International Tumor Bank)….
Global Translational
Processes
Multistep Process: 7 major steps
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1. Identification of Gene abnormalities
2. Determination of relevance in human
cancers
3. Pathway Identification
4. Identification of therapeutic interventions
5. Identifications of patients sub-populations
with given abnormality / Tests
6. Identification of predictive factors / Tests
7. Pivotal clinical development
Translationnal Multistep Process
(7 of 7)
 Pivotal Global Clinical Development
 Acces to multiple targeted subpopulations in a
timely fashion for proof of concept in humans
CIRG
First Academic Global
Translational Intergroup
Meeting the Challenges
 Phenomenal acceleration of new compounds
 Emergence of targeted therapies in subpopulations
 Concept of biology based individualized therapy
 Need to define new models of development and
define new translational strategies
 Patient Access
 Overall stable number of patients
 Targeted therapies: Need to study subpopulations
 Need for new processes for developing new drugs
Summary: Science is our guide
 BCIRG and CIRG were created to
meet that need
 The concept has been proven to
work
 Integrated Translational
approach
 Academic Global Translational
collaboration