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American Society of Clinical Oncology Annual Meeting 2010 Chicago, Illinois - June 04-08, 2010

American Society of Clinical Oncology Annual Meeting 2010 Chicago, Illinois - June 04-08, 2010.

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American Society of Clinical Oncology Annual Meeting 2010 Chicago, Illinois - June 04-08, 2010

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  1. American Society of Clinical Oncology Annual Meeting 2010 Chicago, Illinois - June 04-08, 2010 FOLFOXIRI plus bevacizumab (BV) vs FOLFIRI plus BV asfirst-line treatment ofmetastaticcolorectalcancer (MCRC): preliminarysafetyresultsof the phase III randomized “TRIBE” studyby the Gruppo Oncologico Nord-Ovest (GONO). Alfredo Falcone1,2, FotiosLoupakis1,2, Samanta Cupini3, Enrico Cortesi4, Angela Buonadonna5, Gianluca Tomasello6, Maria Banzi7, Monica Ronzoni8, Alberto Zaniboni9, Gianluca Masi1,2. 1. U.O. Oncologia Medica 2 Universitaria, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy; 2. Dipartimento di Oncologia, dei Trapianti e delle Nuove Tecnologie in Medicina, Università di Pisa, Italy; 3.U.O.Oncologia Medica, Azienda USL-6, Istituto Toscano Tumori, Livorno, Italy ; 4. Dipartimento di Oncologia Medica, Università di Roma La sapienza, Roma, Italy ; 5. Dipartimento di Oncologia Medica, Istituto Nazionale Tumori, Aviano, Italy; 6. Divisione di Medicina e Oncologia Medica, Azienda Istituti Ospitalieri di Cremona, Cremona, Italy; 7. Arcispedale Santa Maria Nuova, Reggio Emilia, Italy; 8. Dipartimento di Oncologia, Istituto Scientifico San Raffaele, Milano, Italy; 9. Fondazione Poliambulanza, Brescia, Italy

  2. Rationale • The combination of BV with cytotoxic drugs is an efficacious strategy in the treatment of mCRC. • Hurwitz H, N Eng J Med 2004 • Giantonio B, J Clinoncol 2007 • Saltz L, J ClinOncol 2008 • The triple drug combination FOLFOXIRI demonstrated increased activity and efficacy over FOLFIRI in a randomized trial. • Falcone A, J ClinOncol 2007 • The combination of FOLFOXIRI plus BV demonstrated promising results in phase II. • Masi G, ESMO 2009

  3. Study Design R A N D O M FOLFIRI + BV 5-FU + BV • Stratification • Center • PS 0 vs 1-2 • Adjuvant CT FOLFOXIRI + BV 5-FU + BV • INDUCTION TX • up to 12 cycles • or PD • or unacceptable toxicity • or patient’s refusal • MAINTENANCE TX • until PD • or intolerable toxicity • or patient’s refusal

  4. FOLFOXIRI + BEVACIZUMAB: INDUCTION SCHEDULE Day 1 Day 2 & Day 3 BV 5 mg/Kg CPT-11 165 mg/sqm Oxaliplatin 85 mg/sqm L-LV 200 mg/sqm 5FU flat continuous infusion 3200 mg/sqm 30 min 1 hour 2 hours 48 hours Repeated every 2 weeks

  5. FOLFIRI + BEVACIZUMAB: INDUCTION SCHEDULE Day 1 Day 2 & Day 3 BV 5 mg/Kg CPT-11 180 mg/sqm L-LV 200 mg/sqm 5FU bolus 400 mg/sqm 5FU flat continuous infusion 2400 mg/sqm 30 min 90 min bolus 48 hours Repeated every 2 weeks

  6. 5FU/LV + BEVACIZUMAB: MAINTENANCE SCHEDULE Day 1 Day 2 & Day 3 BV 5 mg/Kg L-LV 200 mg/sqm 5FU flat continuous infusion 2400 - 3200 mg/sqm 30 min 90 min 48 hours Repeated every 2 weeks

  7. Maintenance Treatment: Schedules INDUCTION TX MAINTENANCE TX 5-FU/LV + BV BV 5 mg/kg 30-min d.1 L-LV 200 mg/m22-h d.1 5FU 400 mg/m2 bolus d.1 5FU 2400 mg/m2 46-h CI d.1 q. 2 wks x 12 cycles FOLFIRI + BV 5-FU/LV + BV BV 5 mg/kg 30-min d.1 L-LV 200 mg/m2 2-h d.1 5FU 3200 mg/m2 48-h CI d.1 q. 2 wks x 12 cycles FOLFOXIRI + BV

  8. Study Objectives • PRIMARY • Progression free survival • SECONDARY • Overall response rate • Duration of response • R0 surgery of metastases • Overall survival • Safety profile • Potential markers predictive of bevacizumab activity

  9. Maininclusioncriteria • Histologically proven metastatic colorectal cancer • Not resectable disease • Not previous chemotherapy for metastatic disease • At least one measurable lesion according to RECIST criteria • Age 18-75 years • ECOG PS ≤ 2 if age < 71 years; ECOG PS = 0 if aged 71-75 years • Previous adjuvant therapy containing oxaliplatin or bevacizumab is allowed if more than 12 months have elapsed between the end of adjuvant therapy and first relapse

  10. Mainexclusioncriteria • History or evidence of CNS disease unless adequately treated • Serious, non-healing wound, ulcer, or bone fracture • Evidence of bleeding diathesis or coagulopathy • Clinically significant cardiovascular disease (cerebrovascular accidents ≤6 months, myocardial infarction ≤ 6 months, unstable angina, NYHA grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication). • Uncontrolled hypertension • Treatment with anticoagulants for therapeutic purposes • Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study treatment start • Lack of physical integrity of the upper gastrointestinal tract, malabsorption syndrome

  11. Statistics • The primary study end-point is Progression Free Survival • Previous trials have shown that the median PFS of MCRC pts treated in first-line with bevacizumab in combination with a fluoropyrimidine-based doublet (as FOLFIRI) is about 11 months. • With the use of a two-sided, unstratified log-rank test with a type I error of 0.05, we determined that 379 events (disease progression or death from any cause) would be required for an 80% power to detect a hazard ratio for progression of 0.75. • With a 1:1 randomization of assignment to study groups and considering a total duration of the study of 54 months we estimated that we would need to enroll 450 patients to observe 379 events. • The primary statistical analysis of efficacy will be the performed according to the intention-to-treat principle.

  12. Dose Reductions and Delays Criteria: Chemotherapy

  13. Dose Reductions and Delays Criteria: Bevacizumab

  14. Safety Interim Analysis • At the time of the present analysis, 268 patients have been enrolledinto the study: • Arm A: FOLFIRI + BV: 133 • Arm B: FOLFOXIRI + BV: 135 • The objective of this interim analysis is to evaluate safety among the first 150 patients enrolled: • Arm A: FOLFIRI + BV: 74 • Arm B: FOLFOXIRI + BV: 76 • All toxic events are gradedaccording to NCI-CTC version 3.0.

  15. Patients Characteristics

  16. Maximum Per Patient Non-Haematological Toxicities during INDUCTION TX

  17. Maximum Per Patient Haematological Toxicities during INDUCTION TX

  18. Maximum Per Patient Cardiovascular Toxicities during INDUCTION TX

  19. Maximum Per Cycle Toxicities during INDUCTION TX

  20. Serious Adverse Events (during INDUCTION Treatment)

  21. Possibly Tx-related Deaths (during INDUCTION Treatment) * based on investigators’ judgment

  22. Dose Reductions and Treatment Delays due to Toxicities during INDUCTION TX

  23. Supportive Therapies during INDUCTION TX *G-CSF, Granulocyte-Colony Stimulating Factor **ESA, Erithropoiesis-Stimulating Agents ***LMWH, Low Molecular Weight Heparin

  24. Maximum Per Patient Toxicities during MAINTENANCE TX

  25. Conclusions • The study is still ongoing • Accrual updated at May 31st 2010 is 272 patients • These preliminary results demonstrate that both treatment arms are safe and feasible • The side-effects occur with the expected incidence and there were not unexpected toxicities

  26. Enrolling Centers

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