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The MINDACT trial: the 1st multinational prospective oncogenomic trial

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.

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The MINDACT trial: the 1st multinational prospective oncogenomic trial

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  1. The MINDACT trial: the 1st multinational prospective oncogenomic trial F. Cardoso, MD TRANSBIG Scientific Director Head, Breast Cancer Unit Champalimaud Cancer Center, Lisbon, Portugal

  2. I have no conflict of interests to disclose related to this talk

  3. BREAST CANCER RESEARCH IN EUROPE 2004 1996 Fragmentation Coordi nation Founding of the Breast International Group (BIG) Better outcomes for women TRANSBIG • 44 research groups in 38 countries • Over 85,000 patients in >30 studies

  4. THE TRANSBIG CONCEPT Large trials comparing treatments A vs B vs C Tailored trials asking biologically relevant questions Successful transition ? • Reinforced dialogue with scientists • Reinforced dialogue with surgeons, • pathologists,radiologists • New models of collaboration with P.I. • Independent funding EMPIRICAL APPROACH “TAILORED” APPROACH

  5. N Engl J Med, Vol 347 (25), Dec. 2002 70 prognosis genes Tumor samples Metastases: white=+ Development of 70 gene expression profile Tumor samples of known clinical outcome Unbiased full genome gene expression analysis Prognosis reporter genes Distant metastases group No distant metastases group ~4% die of breast cancer ~96% survive breast cancer Good signature ~50% die of breast cancer ~50% survive breast cancer Poor signature Courtesy & adapted from L van ‘t Veer

  6. A 3-STEP PROJECT Development of 70-gene prognostic signature (MammaPrint ™) Independent validation study on archive material MINDACT trial STEP 1 STEP 2 STEP 3 Levels of evidence for biomarker studies E.U. GRANT, 6th Framework Programme

  7. EORTC 10041 BIG 3-04 trial MINDACT TRIAL DESIGN 6,000 Node - & 1-3 N+ women Evaluate Clinical-Pathological risk and 70-gene signature risk 55% 32% 13% N=780 N=3300 Discordant cases Clinical-pathological and 70-gene both LOW risk Clinical-pathological and 70-gene both HIGH risk Clin-Path HIGH 70-gene LOW Clin-Path LOW 70-gene HIGH R-T N=1920 Use Clin-Path risk to decide Chemo or not Use 70-gene risk to decide Chemo or not Chemotherapy Endocrine therapy Potential CT sparing in 10-15% pts

  8. The Radiologist The Surgeon The (research) Nurse The Radiotherapist The Pathologist The Medical Oncologist The Patient Good signature Low risk Poor signature High risk The Basic Researcher The Advocate … MINDACT

  9. A GOLDMINE FOR RESEARCH FROZEN TUMOR SAMPLES(remaining after RNA extraction for the MINDACT trial) PARAFFIN-EMBEDDED TUMOR SAMPLES(after TMA construction) SERUM & BLOOD SAMPLES FOR FUTURE RESEARCH Independent biological materials bank Policy for access to samples and/or data

  10. COORDINATING TRANSBIG & MINDACTProblems & Solutions • Scientific issues • Validation Phase • Clinical Trial • Logistical issues • Ethical, Legal & Intellectual property rights issues • Economic issues • Communication issues • Other issues

  11. COORDINATING TRANSBIG & MINDACTProblems & Solutions • Scientific issues • Validation Phase • Clinical Trial • Logistical issues • Ethical, Legal & Intellectual property rights issues • Economic issues • Communication issues • Other issues

  12. COMPLEX LOGISTICS 4 possible ICFs Real-time gene profiling …

  13. EORTC-BIG MINDACT: BIOLOGICAL / DATA FLOWCHART Biological material flow MINDACT - RNA MINDACT – Blocks/TMAs MINDACT – Serum/Blood Center A1 COUNTRY A Center A2 Center A3 Center B1 COUNTRY B NKI Center B2 AGENDIA Center C1 Center C2 COUNTRY C MILAN Center C3 Center C1 COUNTRY D Biobank Center C1 Center C1

  14. TRANSBIG/MINDACT: INFORMATION / DATA FLOWCHART Microarray data EORTC DATA CENTER NKI AGENDIA TRANSBIG SECRETARIAT SIB, Lausanne WEB-BASED SYSTEM MINDACT COURIER I.D.D.I. MINDACT - 70 genes PARTICIPATING CENTERS MINDACT - complex arrays MINDACT - Clinical data TRANSBIG - Other information

  15. COMPLEX LOGISTICS: POTENTIAL SOLUTIONS • AT THE CENTRAL COORDINATION LEVEL: • MINDACT Logistics Pilot (7 European countries) • Dedicated logistics working group • Development of a web-based system • Development of SOPs and guidelines • Development of ready-to-use specific “sample collection kit” • Development of “user-friendly tools”: • for the investigator & research nurse (e.g. leaflets) • for the patient • Investigators & research nurses training meetings • AT THE LOCAL HOSPITAL LEVEL: • Strong inter-department collaboration • Crucial role of research nurse

  16. F F A A A A B B B B D E D D D C E E E C C C 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

  17. INTERNATIONAL SOPs BIG-NABCG Recommendations B Leyland-Jones et al, JCO J Clin Oncol. 2008 Dec 1; 26(34):5638-44

  18. WEB-BASED SYSTEM-1

  19. WEB-BASED SYSTEM-1

  20. WEB-BASED SYSTEM-1 DETAILED SOPs

  21. LEAFLETS • Inclusion criteria • Sample collection & handling • Timelines • …

  22. ADAPTED FOR EACH INDIVIDUAL CENTER

  23. MINDACT DVD

  24. 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

  25. POLICY FOR ACCESS TO SAMPLES AND/OR DATA FROM MINDACT Publicly available online BIG-TRANSBIG HQ– Used with permission

  26. MINDACT EXAMPLE Total expected costs: €37, 000,000 Granted by EU: € 7, 000,000 EU Biotechnology Companies (Agendia) Pharmaceutical Industry National Resources Other Grants FUNDING FOR INTERNATIONAL TRIALS: A HUGE HURDLE • Most funding agencies only fund national projects or national patients in international projects • Most foundations and charities have the same policy • No health-specific international funding body in Europe (only EU)

  27. COORDINATING TRANSBIG & MINDACTProblems & Solutions Communication issues • TRANSBIG is a big and heterogeneous consortium • Different countries, cultures and priorities • Involvement of commercial companies in an academic research consortium PROBLEMS: INEVITABLE LEADS TO

  28. COMMUNICATION PROBLEMS

  29. MISINTERPRETATION PROBLEMS

  30. MARRIAGE COUNSELING COMMUNICATION PROBLEMS: SOLUTIONS TRANSBIG Coordinator

  31. It’s difficult but it is POSSIBLE!

  32. PILOT PHASE OF THE MINDACT TRIAL N=800 women A/ EVALUATION OF PRE-ENROLLMENT EVENTS • proportion of samples with « good » quality RNA • proportion of Node + / Node - disease • proportion of Node – cases entering MINDACT • proportion of eligible patients not randomized B/ EVALUATION OF POST-FIRST RANDOMIZATION EVENTS DECISION BASED ON CLINICALPATHOLOGICAL DECISION BASED ON GENE PROFILE RESULTS PRESENTED AT EBCC-7 ACCESS PROTOCOL VIOLATIONS

  33. MINDACT PILOT PHASE Logistics feasible. 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 -) Older Fewer ER-, fewer HER2+ Tumor size smaller Tumor grade comparable Expected fraction of clinical high risk patients 77% vs. observed 42.4%. Clinicians/pts comply with the protocol in the “70-gene signature /genomic arm”. Statistically significant difference is observed reduction in CT administration. 34 Rutgers et al, EBCC-7

  34. WAS CHEMO ACTUALLY GIVEN?COMPLIANCE! 92% assigned to CT, received 100% assigned to no CT, did not receive Overall no significant difference in toxicity between different chemo regimens

  35. MINDACT RECRUITMENT As of 25.10.2010 Screened: 7777 pts Enrolled: 4536 pts ~ 200 pts/month 100 centers/9 countries

  36. Genomics Proteomics Transcriptomics Immunohistochemistry, signalling pathways ……….?? COLLECT STORE SHARE

  37. ACKNOWLEDGEMENTS -1 ALL PATIENTS EORTC MINDACT Team BIG-TRANSBIG Team

  38. ACKNOWLEDGEMENTS – 2: FUNDING Brussels Breast Cancer Walk-Run & American Women’s Club of Brussels ** Agendia’s investment is in services provided and not direct funds

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