the mindact trial: the 1st multinational prospective oncogenomic trial
DESCRIPTION
The MINDACT trial: the 1st multinational prospective oncogenomic trial. F. Cardoso, MD TRANSBIG Scientific Director Head, Breast Cancer Unit Champalimaud Cancer Center, Lisbon, Portugal. I have no conflict of interests to disclose related to this talk. BREAST CANCER RESEARCH IN EUROPE. - PowerPoint PPT PresentationTRANSCRIPT
The MINDACT trial: The MINDACT trial: the 1st multinational prospective oncogenomic trialthe 1st multinational prospective oncogenomic trial
F. Cardoso, MDF. Cardoso, MDTRANSBIG Scientific DirectorTRANSBIG Scientific Director
Head, Breast Cancer UnitHead, Breast Cancer UnitChampalimaud Cancer Center, Lisbon, PortugalChampalimaud Cancer Center, Lisbon, Portugal
I have no conflict of interests to disclose related to this talk
BIG-TRANSBIG HQ– Used with permissionBIG-TRANSBIG HQ– Used with permission
BREAST CANCER RESEARCH IN EUROPEBREAST CANCER RESEARCH IN EUROPE
FragmentationFragmentation Coordi nationCoordi nation
Founding Founding of the of the
Breast International GroupBreast International Group(BIG)(BIG)
19961996
• 44 research groups in 38 44 research groups in 38 countriescountries
• Over 85,000 patients in Over 85,000 patients in >30 studies>30 studies
Better Better outcomes for outcomes for
womenwomen
TRANSBIGTRANSBIG
20042004
BIG-TRANSBIG HQ– Used with permissionBIG-TRANSBIG HQ– Used with permission
THE TRANSBIG CONCEPTTHE TRANSBIG CONCEPT
LargeLargetrialstrials
comparingcomparingtreatments treatments
A vs BA vs Bvs Cvs C
TailoredTailoredtrialstrials
askingaskingbiologicallybiologically
relevantrelevantquestionsquestions
EMPIRICAL EMPIRICAL APPROACHAPPROACH
Successful transition ?Successful transition ?
““TAILORED” TAILORED” APPROACHAPPROACH
• Reinforced dialogue with Reinforced dialogue with scientistsscientists• Reinforced dialogue with Reinforced dialogue with surgeonssurgeons,, pathologistspathologists,, radiologistsradiologists• New models of collaboration with New models of collaboration with P.I.P.I.• Independent fundingIndependent funding
Tumor samples of known clinical outcome
No distant metastasesgroup
Unbiased full genome gene expression
analysis
Distant metastasesgroup
70 prognosis genes
Tu
mo
r s
amp
les
Metasta
ses: wh
ite=
+
Prognosis reporter genes
Development of 70 geneexpression profile
Good signature
Poor signature
~4% die of breast cancer~96% survive breast cancer
~50% die of breast cancer~50% survive breast cancer
N Engl J Med, Vol 347 (25), Dec. 2002
Courtesy & adapted from L van ‘t Veer
BIG-TRANSBIG Secretariat– Used with permission
Development of 70-gene
prognostic signature
(MammaPrint ™)
STEP 1STEP 1
IndependentIndependentvalidation study on validation study on
archive materialarchive material
STEP 2STEP 2
MINDACT trial
STEP 3STEP 3
Levels of evidence for biomarker studies
E.U. GRANT, 6E.U. GRANT, 6thth Framework Programme Framework Programme
A 3-STEP PROJECT A 3-STEP PROJECT
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IMPROVED RISK ASSESSMENT OF EARLY BREAST IMPROVED RISK ASSESSMENT OF EARLY BREAST CANCER THROUGH GENE EXPRESSION PROFILINGCANCER THROUGH GENE EXPRESSION PROFILING
microarraymicroarrayGeneGene--expression profileexpression profile
Good signature
Poor signature
N N EnglEngl J Med, J Med, VolVol 347 (25), Dec. 2002347 (25), Dec. 2002
~4% die of breast cancer~96% survive breast cancer
~50% die of breast cancer~50% survive breast cancer
BIGBIG--TRANSBIG HQTRANSBIG HQ–– Used with permissionUsed with permissionJuly 2008July 2008-- ConfidentialConfidential
Audited Audited clinical clinical
datadata
INDEPENDENT VALIDATION : DESIGNINDEPENDENT VALIDATION : DESIGN
RNA
Achieved Achieved n = 307n = 307
Target Target n = 400n = 400
AmsterdamAmsterdam
Gene expression Gene expression profilingprofiling
•• Agilent platformAgilent platform•• 7070--gene prognostic gene prognostic
custom designed custom designed chipchip
High or low gene signature
risk
Clinical dataClinical data
«« LocalLocal »» pathological datapathological data
BrusselsBrusselsComparison of Comparison of clinical clinical vsvs gene gene
signaturesignatureassessment of assessment of prognostic riskprognostic risk
EndpointsEndpoints1. TDM1. TDM2. OS 2. OS 3. DMFS, DFS3. DMFS, DFS
Tissue samplesTissue samples UK (GuyUK (Guy’’s, Oxford) : s, Oxford) :
1984 => 19961984 => 1996 France (IGR, CRH) : France (IGR, CRH) :
1978 => 19981978 => 1998 Sweden (Karolinska) : Sweden (Karolinska) :
1980 => 19901980 => 1990
•• Node negative, untreatedNode negative, untreated•• < 60 years old< 60 years old•• > 5 years follow> 5 years follow--upup•• T1, T2T1, T2•• Tumor cell % > 50%Tumor cell % > 50%
Centrally Centrally reviewed reviewed path data path data
(Milan)(Milan)
Buyse et al, JNCI 98: 1183-1192, 2006
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OVERALL SURVIVAL by GENE SIGNATURE RISKOVERALL SURVIVAL by GENE SIGNATURE RISKAmsterdam/Agendia SignatureAmsterdam/Agendia Signature
Year
Pro
ba
bili
ty0
.00
.20
.40
.60
.81
.0
0 2 4 6 8 10 12 14
Patients Events Risk group
113 16 Genetic low risk194 66 Genetic high risk
113 112 105 101 98 82 69 45 38 CLR194 185 168 147 130 110 90 53 39 CHR
Number at risk
10-year OS89% (81%-94%)
10-year OS70% (62%-76%)
Average Survival HR Average Survival HR 2.662.66BIGBIG--TRANSBIG HQTRANSBIG HQ–– Used with permissionUsed with permissionJuly 2008July 2008-- ConfidentialConfidential
ADJUVANT! ONLINE FOR BREAST CANCERADJUVANT! ONLINE FOR BREAST CANCERUpdated versionUpdated version
“Clinical low risk” defined as predicted 10-year BC survival
probability
88% for ER+ patients
92% for ER- patients
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Evaluate Clinical-Pathological risk and 70-gene signature risk
Clinical-pathological and 70-gene both
HIGH risk
Discordant casesClin-Path HIGH70-gene LOW
Clin-Path LOW70-gene HIGH
Clinical-pathological and 70-gene both LOW
risk
Use Clin-Path risk to decide Chemo or not
Use 70-gene risk to decide Chemo or not
55% 32% 13%
R-T
Chemotherapy
N=3300 N=780
Endocrine therapy
EORTC 10041 BIG 3-04 trial MINDACT TRIAL DESIGN6,000 Node - & 1-3 N+ women
N=1920
Potential CT sparing in 10-15% pts
Good signatureLow risk
Poor signatureHigh risk
The Surgeon
The Basic Researcher
The Medical Oncologist
The Radiotherapist
The (research) Nurse
The Pathologist
The Radiologist
The Patient
The Advocate
…
MINDACT
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FROZEN TUMOR SAMPLES (remaining after RNA extraction for the MINDACT trial)
PARAFFIN-EMBEDDED TUMOR SAMPLES (after TMA construction)
SERUM & BLOOD SAMPLES
FOR FUTURE RESEARCH
A GOLDMINE FOR RESEARCHA GOLDMINE FOR RESEARCH
Independent biological materials bankPolicy for access to samples and/or data
COORDINATING TRANSBIG & MINDACTProblems & Solutions
I. Scientific issues• Validation Phase• Clinical Trial
II. Logistical issues
I. Ethical, Legal & Intellectual property rightsIntellectual property rights issues
III. Economic issues
IV. Communication issues
V. Other issues
COORDINATING TRANSBIG & MINDACTProblems & Solutions
I. Scientific issues• Validation Phase• Clinical Trial
II. Logistical issues
I. Ethical, Legal & Intellectual property rightsIntellectual property rights issues
III. Economic issues
IV. Communication issues
V. Other issues
COMPLEXLOGISTICS
MINDACT 10041
Discordant
CT ChemotherapyR-T Treatment decision Randomization based on genomic vs clinical prognosis R-C Chemotherapy Randomization of Anthracycline based CT (FEC D for N+) vs
Docetaxel/CapecitabineR-E Endocrine treatment Randomization Letrozole vs Tamoxifen followed by
LetrozoleHR Hormone receptorPIS & IC Patient information sheet and informed consent
CT R-C
HR -
R-E
High/HighLow/LowR-T
No CT
HR +HR -
HR +
Visit surgeon (T1, T2 or operable T3 & M0)
screening PIS & IC, Screening
0 to 3 positive nodes
Screening
SurgeryTumor sample shipment, RNA extraction, microarray analysis,
local pathology, TNM, lymph node status, HR status
De
lay
betw
ee
n s
urg
ery
an
d s
tart
of
syst
emic
tre
atm
ent i
dea
lly n
ot m
ore
tha
n 8
we
eks
, ca
n n
ot
be
> 1
2 w
eeks
Signing of PIS & IC 1 & EnrollmentGenomic/Clinical Prognosis review & randomization
4 possible ICFsReal-time gene
profiling…
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EORTC-BIG MINDACT: BIOLOGICAL / DATA BIOLOGICAL / DATA FLOWCHARTFLOWCHART
COUNTRY A
COUNTRY B
COUNTRY C
Center A1
Center A3
Center A2
Center B1
Center B2
Center C1
Center C3
Center C2
NKI
AGENDIA
MILAN
BiobankCOUNTRY D
Biological material flow MINDACT – Blocks/TMAs
MINDACT - RNA
MINDACT – Serum/Blood
Center C1
Center C1
Center C1
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TRANSBIG/MINDACT: INFORMATION / DATA FLOWCHARTTRANSBIG/MINDACT: INFORMATION / DATA FLOWCHART
EORTC DATA CENTER
TRANSBIG SECRETARIAT
I.D.D.I.
PARTICIPATINGCENTERS
NKI
AGENDIA
SIB, Lausanne
COURIER
MINDACT - Clinical data
MicroarrayMicroarray data data
TRANSBIG - Other information
MINDACT - 70 genes
MINDACT - complex arrays
WEB-BASED SYSTEMMINDACT
AT THE CENTRAL COORDINATION LEVEL:
1. MINDACT Logistics Pilot (7 European countries)2. Dedicated logistics working group3. Development of a web-based system4. Development of SOPs and guidelines5. Development of ready-to-use specific “sample collection kit”6. Development of “user-friendly tools”:
a) for the investigator & research nurse (e.g. leaflets)b) for the patient
7. Investigators & research nurses training meetings
AT THE LOCAL HOSPITAL LEVEL:
1. Strong inter-department collaboration2. Crucial role of research nurse
COMPLEX LOGISTICS: POTENTIAL SOLUTIONS
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TISSUE HANDLING
SOPs for every step
Sampling kit (centrally prepared)
Pathologist training (clear learning curve)
Dedicated international & experienced courier company (involved in all steps & from the beginning)
Web-based tracking system
Regular meetings between partners
AB
C
D
E
F
AB
C
D
E
AB
C
D
E
AB
C
D E
F
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INTERNATIONAL SOPs
BIG-NABCG RecommendationsB Leyland-Jones et al, JCO J Clin Oncol. 2008 Dec 1; 26(34):5638-44
WEB-BASED SYSTEM-1
WEB-BASED SYSTEM-1
DETAILED SOPs
WEB-BASED SYSTEM-1
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BLOOD SAMPLES
Centrifuge for 5’ at 3000 rpm
At room temperatureAfter 30’ of clotting at room temperature
Serum
FREEZE- 80°
0.5 ml aliquots into max. 10 cryovials, yellow yellow inserts, sample ID sticker, register time taken from centrifugation to storage
2x5 ml into Greiner KG456071 labelled vacuette tubes
Shipment of serum byWC to TBBMB
at the end of recruitment
WC - World CourrierTBBMB -TRANSBIG Biological materials bank in Brussels
BIG-TRANSBIG HQ– Used with permissionMarch 2009 - Confidential
FROZEN TUMOR BIOPSIES
6 mm punch biopsy, cryovials are emptyNo tissue TEK or OCT solution
Remove to zip lock bag and keep in dry ice if not immediately stored at -80°C FREEZE - 80°
Dip gently in liquid nitrogen, 1 minute
1
4
3
5
2
APPLY LABEL BEFORE FREEZING- unique sample ID linked to patient’s seq ID
•In the operating room the tumor should be placed in an empty container, no fixatives. Max.1 hour between surgery and biopsy, note this time interval•1 or 2 (if possible) punch sample biopsies of the surgically removed tumor•6 mm biopsy, if tumor <1 cm 3 mm biopsy, in the periphery of the tumor•Always use RNase free equipment: Sterile gloves, forceps and tweezers
6
Register the sample and link sample ID to SeqID in the web based platform. This will trigger a pick up signal to World Courier that ships sample to Agendia
www.mindact.org
LEAFLETS
• Inclusion criteria
• Sample collection & handling
• Timelines
• …
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KeyT = Hospital visit / Time pointR = randomizationPIS-IC = Patient information & Informed Consent
A.A. Tumor Diagnosis B. Patient signs screening PIS & ICC. Tumor sample sent to Cancer InstituteD. Local pathology, Lymph node status determination E. RNA quantity & quality good, for 0-3 +ve LN PI told patient eligible
& microarray analysis performedF. Genomic prognostic test performed, result communicated to PI after signing of PIS & IC 1G. Patient returns home with R-C / R-E information to decide on participation.H. Patient signs PIS & IC 2 or 3 and brings/posts it to Center/signs at the start of treatmentI. Patient inclusion in MINDACT and randomization for discordant patients
Cancer Institute microarray
MINDACT study timeline guidelines from diagnosis to start of treatment
Patient receives generalMINDACT informationsurgeon / research nurse
max 8 weeks max 56 days max 84 days
T1 T2 T3a T3b T4Diagnosis Surgery Surgical Oncologist post-op Start
post-op visit visit Treatment
Hospitalization
Signing ofsPIS & IC
Lymph node status known
Information & signingof PIS & IC 1 (Discordant patients are randomized)
MINDACT Discussion
+Proposal for Randomizations according to risk
Chemotherapy and Hormonal therapy
YES/NOFeedback from patient
Signing ofPIS & IC 2 or 3Bring to Center during LVEF visit or post to Center
A. B.
F.
E.
D. G.
F.
H.
RNA QC good
0-3 +ve LN
R I.
C.
V 2p 9-11-07
ADAPTED FOR EACH INDIVIDUAL CENTER
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MINDACT DVD
COORDINATING TRANSBIG & MINDACTProblems & Solutions
Ethical, Legal & IPR issues
SOLUTIONS :
Ethical-Legal Committee created
IPR working group formed
External experts help looked for
Specialized lawyer hired (but very costly)
Involvement of patients & patients advocates in all parts of the project from the beginning
Study different laws and regulations in each involved country
Establish as early as possible policy for access to samples/data
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TRANSBIG HQTRANSBIG HQ
proposal
transmitsto
Independent Review CommitteeIndependent Review CommitteeChair IRC + TRANSBIG Scientific Director
designates reports to
Reviewers from IRC
reports to
TRANSBIG Ethical-Legal Committee
ScientificRanking
Executive CommitteeExecutive Committee(Common to TRANSBIG & MINDACT)(Common to TRANSBIG & MINDACT)
POLICY FOR ACCESS TO
SAMPLES AND/OR DATA FROM
MINDACT
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Executive CommitteeExecutive Committee(Common to TRANSBIG & MINDACT)(Common to TRANSBIG & MINDACT)
Transmitsfor finalapproval
60% Majority Approval 60% Majority Approval ++ 60% Majority Approval60% Majority Approval
MINDACTMINDACTSteeringSteering
CommitteeCommittee
TRANSBIGTRANSBIGSteeringSteering
CommitteeCommittee
75% Super Majority is required for External
Proposalsduring “restricted” period
PRACTICAL IMPLEMENTATIONPRACTICAL IMPLEMENTATION
Official written approvalOfficial written approvalby Executive Committeeby Executive Committee
Official written approval Official written approval by EORTC Regulatory Unit by EORTC Regulatory Unit
Publicly available online
1. Most funding agencies only fund national projects or national patients in international projects
2. Most foundations and charities have the same policy3. No health-specific international funding body in Europe (only EU)
FUNDING FOR INTERNATIONAL TRIALS: A HUGE HURDLE
EU funding
OtherBiotechnology Companies (Agendia)Pharmaceutical Industry
National ResourcesOther Grants
EUEUMINDACT EXAMPLE
Total expected costs: €37, 000,000
Granted by EU: € 7, 000,000
• TRANSBIG is a big and heterogeneous consortiumTRANSBIG is a big and heterogeneous consortium• Different countries, cultures and priorities Different countries, cultures and priorities • Involvement of commercial companies in an academic Involvement of commercial companies in an academic
research consortiumresearch consortium
COORDINATING TRANSBIG & MINDACTProblems & Solutions
Communication issues
PROBLEMS:
INEVITABLE LEADS TO
COMMUNICATION PROBLEMS
MISINTERPRETATION PROBLEMS
MARRIAGE COUNSELING
COMMUNICATION PROBLEMS: SOLUTIONS
TRANSBIG Coordinator
It’s difficult but it is POSSIBLE!
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PILOT PHASE OF THE MINDACT TRIAL PILOT PHASE OF THE MINDACT TRIAL
N=800 womenN=800 women
A/ EVALUATION OF PRE-ENROLLMENT EVENTSA/ EVALUATION OF PRE-ENROLLMENT EVENTSA/ EVALUATION OF PRE-ENROLLMENT EVENTSA/ EVALUATION OF PRE-ENROLLMENT EVENTS
B/ EVALUATION OF POST-FIRST RANDOMIZATION EVENTSB/ EVALUATION OF POST-FIRST RANDOMIZATION EVENTSB/ EVALUATION OF POST-FIRST RANDOMIZATION EVENTSB/ EVALUATION OF POST-FIRST RANDOMIZATION EVENTS
• proportion of samples with « good » quality RNAproportion of samples with « good » quality RNA• proportion of Node + / Node - diseaseproportion of Node + / Node - disease• proportion of Node – cases entering MINDACTproportion of Node – cases entering MINDACT• proportion of eligible patients not randomizedproportion of eligible patients not randomized
DECISION BASED ON CLINICALPATHOLOGICALDECISION BASED ON CLINICALPATHOLOGICAL DECISION BASED ON GENE PROFILEDECISION BASED ON GENE PROFILE
ACCESS PROTOCOL VIOLATIONSACCESS PROTOCOL VIOLATIONS
RESULTS PRESENTED AT EBCC-7
34
MINDACT PILOT PHASE1. Logistics feasible.2. Change in biology of breast cancer or more screening
detected?As a consequence, the patient population in the trial as compared to the patients from the validation series (all node -)
OlderFewer ER-, fewer HER2+Tumor size smallerTumor grade comparable
Expected fraction of clinical high risk patients 77% vs. observed 42.4%.
3. Clinicians/pts comply with the protocol in the “70-gene signature /genomic arm”.
4. Statistically significant difference is observed reduction in CT administration.
Rutgers et al, EBCC-7
35
WAS CHEMO ACTUALLY GIVEN?COMPLIANCE!
Chemotherapy administration (best current knowledge) by assignment to chemotherapy
Treatment decision outcome
chemo (N=309)
no chemo****
(N=491) Total
(N=800)
N (%) N (%) N (%)
Chemo received
No 21* (6.8) 472 (96.1) 493 (61.6)
Yes 268 (86.7) 19** (3.9) 287 (35.9)
Unknown 20*** (6.5) 0 (0.0) 20 (2.5)
92% assigned to CT, received 100% assigned to no CT, did not receive
Overall no significant difference in toxicity between different chemo regimens
As of 25.10.2010
Screened: 7777 ptsEnrolled: 4536 pts
~ 200 pts/month100 centers/9 countries
MINDACT RECRUITMENT
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GenomicsGenomics
ProteomicsProteomics
TranscriptomicsTranscriptomics
Immunohistochemistry,Immunohistochemistry,
signalling pathwayssignalling pathways
……….??
COLLECT
STORE
SHARE
ACKNOWLEDGEMENTS -1ACKNOWLEDGEMENTS -1
BIG-TRANSBIG Team EORTC MINDACT Team
ALL
PATIENTS
BIG-TRANSBIG Secretariat– Used with BIG-TRANSBIG Secretariat– Used with permissionpermission
Fund providerFund provider (EUR)(EUR)
European CommissionEuropean Commission 7.000.0007.000.000
NovartisNovartis 11.000.00011.000.000
F. Hoffmann-La RocheF. Hoffmann-La Roche 7.667.1657.667.165
Sanofi-Aventis GroupSanofi-Aventis Group 2.812.3502.812.350
Eli LillyEli Lilly 240.000240.000
Veridex LLCVeridex LLC 187.234187.234
Agendia**Agendia** 10.000.00010.000.000
Breast Cancer Research FoundationBreast Cancer Research Foundation 900.000900.000
EBCC-EBCC-Breast Cancer Working Group - asbl Breast Cancer Working Group - asbl 400.000400.000
Susan G. Komen for the CureSusan G. Komen for the Cure 101.630101.630
Jacqueline Seroussi Memorial FoundationJacqueline Seroussi Memorial Foundation 103.074103.074
Fondation Contre le Cancer (BELGIUM)Fondation Contre le Cancer (BELGIUM) 250.000250.000
UKUK (£49.000) 62.500(£49.000) 62.500
Dutch Cancer Society (KWF)Dutch Cancer Society (KWF) 200.000200.000
Association Le cancer du sein, parlons-en!Association Le cancer du sein, parlons-en! 50.00050.000
** Agendia’s investment is in services provided and not direct funds
ACKNOWLEDGEMENTS – 2: FUNDINGACKNOWLEDGEMENTS – 2: FUNDING
Brussels Breast Cancer Walk-Run & American Women’s Club of Brussels