The MINDACT trial: the 1st multinational prospective oncogenomic trial

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


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


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

BIG-TRANSBIG HQ– Used with permissionBIG-TRANSBIG HQ– Used with permissionFeb 2009Feb 2009- Confidential- Confidential

BIGBIG--TRANSBIG HQTRANSBIG HQ–– Used with permissionUsed with permissionJuly 2008July 2008-- ConfidentialConfidential

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




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


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


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


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


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…

BIG-TRANSBIG BIG-TRANSBIG SecretariatSecretariat– Used with – Used with permissionpermission

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

BIG-TRANSBIG BIG-TRANSBIG SecretariatSecretariat– Used with – Used with permissionpermission

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


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


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

BIG-TRANSBIG HQ– Used with permission

BIG-TRANSBIG HQ– Used with permissionMarch 2009 - Confidential

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

• …


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

BIG-TRANSBIG HQ– Used with permission

MINDACT DVD


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


BIGBIG--TRANSBIG HQTRANSBIG HQ–– Used with permissionUsed with permissionMay 2009May 2009 -- ConfidentialConfidential

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

BIG-TRANSBIG HQ– Used with permissionBIG-TRANSBIG HQ– Used with permissionBIGBIG--TRANSBIG HQTRANSBIG HQ–– Used with permissionUsed with permissionMay 2009May 2009 -- ConfidentialConfidential

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


Communication issues

PROBLEMS:

INEVITABLE LEADS TO

COMMUNICATION PROBLEMS

MISINTERPRETATION PROBLEMS

MARRIAGE COUNSELING

COMMUNICATION PROBLEMS: SOLUTIONS

TRANSBIG Coordinator

It’s difficult but it is POSSIBLE!

BIG-TRANSBIG HQ– Used with permissionBIG-TRANSBIG HQ– Used with permissionMarch 2009March 2009- Confidential- Confidential

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


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

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The MINDACT trial: the 1st multinational prospective oncogenomic trial

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