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FOLFOXIRI plus bevacizumab (BV) vs FOLFIRI plus BV as first- line treatment of metastatic colorectal cancer (MCRC): preliminary safety results of the phase.

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Presentazione sul tema: "FOLFOXIRI plus bevacizumab (BV) vs FOLFIRI plus BV as first- line treatment of metastatic colorectal cancer (MCRC): preliminary safety results of the phase."— Transcript della presentazione:

1 FOLFOXIRI plus bevacizumab (BV) vs FOLFIRI plus BV as first- line treatment of metastatic colorectal cancer (MCRC): preliminary safety results of the phase III randomized “TRIBE” study by the Gruppo Oncologico Nord-Ovest (GONO). Alfredo Falcone 1,2, Fotios Loupakis 1,2, Samanta Cupini 3, Enrico Cortesi 4, Angela Buonadonna 5, Gianluca Tomasello 6, Maria Banzi 7, Monica Ronzoni 8, Alberto Zaniboni 9, Gianluca Masi 1,2. 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 American Society of Clinical Oncology Annual Meeting 2010 Chicago, Illinois - June 04-08, 2010

2 RationaleRationale  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 Clin oncol 2007 Saltz L, J Clin Oncol 2008  The triple drug combination FOLFOXIRI demonstrated increased activity and efficacy over FOLFIRI in a randomized trial. Falcone A, J Clin Oncol 2007  The combination of FOLFOXIRI plus BV demonstrated promising results in phase II. Masi G, ESMO 2009

3 Study Design FOLFIRI + BV FOLFOXIRI + BV Stratification Center PS 0 vs 1-2 Adjuvant CT RANDOM 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 5FU flat continuous infusion 3200 mg/sqm 5FU flat continuous infusion 3200 mg/sqm L-LV 200 mg/sqm L-LV Oxaliplatin 85 mg/sqm Oxaliplatin 2 hours Repeated every 2 weeks CPT mg/sqm CPT hours Day 1 Day 2 & Day 3 1 hour BV 5 mg/Kg BV 30 min FOLFOXIRI + BEVACIZUMAB: INDUCTION SCHEDULE

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

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

7 FOLFIRI + BV FOLFOXIRI + BV Maintenance Treatment: Schedules 5-FU/LV + BV BV5 mg/kg 30-min d.1 L-LV200 mg/m 2 2-h d.1 5FU400 mg/m 2 bolus d.1 5FU 2400 mg/m 2 46-h CI d.1 q. 2 wks x 12 cycles 5-FU/LV + BV BV5 mg/kg 30-min d.1 L-LV200 mg/m 2 2-h d.1 5FU400 mg/m 2 bolus d.1 5FU 2400 mg/m 2 46-h CI d.1 q. 2 wks x 12 cycles 5-FU/LV + BV BV5 mg/kg 30-min d.1 L-LV200 mg/m 2 2-h d.1 5FU 3200 mg/m 2 48-h CI d.1 q. 2 wks x 12 cycles 5-FU/LV + BV BV5 mg/kg 30-min d.1 L-LV200 mg/m 2 2-h d.1 5FU 3200 mg/m 2 48-h CI d.1 q. 2 wks x 12 cycles INDUCTION TX MAINTENANCE TX

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

9 Main inclusion criteria Histologically proven metastatic colorectal cancer Not resectable disease Not previous chemotherapy for metastatic disease At least one measurable lesion according to RECIST criteria Age years ECOG PS ≤ 2 if age < 71 years; ECOG PS = 0 if aged 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 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 Main exclusion criteria

11 StatisticsStatistics 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 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 AT THE START OF CYCLEGRADECPT-11LOHP5-FU WBC< 3.000/mm 3 HOLD UNTIL RESOLUTION Neutrophils< 1.000/mm 3 Platelets< /mm 3 Diarrhea≥ 1 Mucositis≥ 1 Any other NHT≥ 2 HFS3-4100% STOP Neurotoxicity≥ 3100%STOP100% PREVIOUS TOXICITYGRADECPT-11LOHP5-FU Febrile neutropenia475% 100% Thrombocytopenia3-475% 100% Diarrhea375%100%75% Diarrhea450%100%50% Mucositis3100% 75% Mucositis4100% 50%

13 Dose Reductions and Delays Criteria: Bevacizumab TOXICITYGRADEBV Hypertension3STOP if uncontrolled despite appropriate tx Hypertension4STOP Hemorrhage2-3HOLD UNTIL RESOLUTION Hemorrhage4STOP Venous thrombosis3-4STOP Arterial thrombosisAnySTOP Congestive heart failure3HOLD UNTIL GRADE ≤2 Congestive heart failure4STOP Proteinuria3HOLD UNTIL GRADE ≤2 Proteinuria4STOP GI perforationAnySTOP Wound dehiscenceAnySTOP

14 Safety Interim Analysis 268 patients have been enrolled  At the time of the present analysis, 268 patients have been enrolled into the study: Arm A: FOLFIRI + BV: 133 Arm B: FOLFOXIRI + BV: 135 the first 150 patients enrolled  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 NCI-CTC version 3.0  All toxic events are graded according to NCI-CTC version 3.0.

15 FOLFIRI + BV 74 pts FOLFOXIRI + BV 76 pts Age, median (range)59 (29-74)58 (29-74) Sex M/F51% / 49%59% / 41% ECOG PS 0/1-289% / 11%87% / 13% Primary Colon/Rectum69% / 31%72% / 28% Primary on site 26%22% Sites of mts 1/≥223%/77%34% /66% Previous adjuvant CT Y/N11% / 89% Previous adjuvant RT Y/N7% / 91%3% / 93% N. of induction treatment cycles administered Median N. of induction treatment cycles per patient 1211 Patients Characteristics

16 FOLFIRI + BV 74 pts FOLFOXIRI + BV 76 pts G1-2G3-4G1-2G3-4 Nausea57%1%51%4% Vomiting20%0%30%5% Diarrhea46%8%50%20% Stomatitis39%5%45%9% Asthenia46%8%59%7% Hand-Foot Syndrome11%0%12%0% Neurotoxicity (grade 2-3)NA22% Maximum Per Patient Non-Haematological Toxicities during INDUCTION TX Maximum Per Patient Non-Haematological Toxicities during INDUCTION TX

17 FOLFIRI + BV 74 pts FOLFOXIRI + BV 76 pts G1-2G3-4G1-2G3-4 Neutropenia24%14%22%47% Febrile Neutropenia-4%-7% Thrombocytopenia8%1%22%3% Anemia51%0%62%1% Maximum Per Patient Haematological Toxicities during INDUCTION TX Maximum Per Patient Haematological Toxicities during INDUCTION TX

18 FOLFIRI + BV 74 pts FOLFOXIRI + BV 76 pts G1-2G3-4G1-2G3-4 Hypertension22%1%17%1% Bleeding27%0%29%3% Venous thrombosis0%8%3%9% Arterial thrombosis0%1%0%3% GI perforation0% 1% Proteinuria19%1%22%1% Ematuria8%1%9%0% Maximum Per Patient Cardiovascular Toxicities during INDUCTION TX Maximum Per Patient Cardiovascular Toxicities during INDUCTION TX

19 FOLFIRI + BV 74 pts FOLFOXIRI + BV 76 pts N. of cycles administered G1-2G3-4G1-2G3-4 Diarrhea22%1%26%3% Stomatitis13%1%14%1% Neutropenia10%3%22%11% Febrile Neutropenia-1%- Thrombocytopenia3%1%8%1% Maximum Per Cycle Toxicities during INDUCTION TX Maximum Per Cycle Toxicities during INDUCTION TX

20 Serious Adverse Events (during INDUCTION Treatment) FOLFIRI 74 pts FOLFOXIRI 76 pts All SAE 11 pts(15%)15 pts(20%) Type of Serious Adverse Events 1 Stroke1 Cardiac Ischemia 1 Sudden Death2 Atrial Flutter 2 Pulmonary Embolism1 Sepsis 1 Deep Vein Thrombosis1 Pneumonia 1 GI Bleeding 1 GI Obstruction1 GI Perforation 3 Diarrhea6 Diarrhea 1 Febrile Neutropenia2 Febrile Neutropenia

21 Possibly Tx-related Deaths (during INDUCTION Treatment) FOLFIRI 74 pts FOLFOXIRI 76 pts Possibly Treatment Related Deaths* 3 pts(4%)2 pts(3%) 1 Stroke1 GI bleeding 2 Pulmonary Embolism1 Sepsis * based on investigators’ judgment

22 FOLFIRI + BV 74 pts FOLFOXIRI + BV 76 pts DOSE REDUCTIONS 5-Fluorouracil5%6% Irinotecan5%9% OxaliplatinNA9% TREATMENT DELAYS 5-Fluorouracil5%21% Irinotecan5%21% OxaliplatinNA21% BV0%12% Dose Reductions and Treatment Delays due to Toxicities during INDUCTION TX

23 Supportive Therapies during INDUCTION TX FOLFIRI + BV 74 pts FOLFOXIRI + BV 76 pts G-CSF*15%26% ESA**3%7% LMWH***11%8% Oral Anticoagulant0% *G-CSF, Granulocyte-Colony Stimulating Factor **ESA, Erithropoiesis-Stimulating Agents ***LMWH, Low Molecular Weight Heparin

24 FOLFIRI + BV 74 pts FOLFOXIRI + BV 76 pts G1-2G3-4G1-2G3-4 Vomiting9%0%1%0% Diarrhea9%0%7%0% Stomatitis11%0%11%0% Hand-Foot Syndrome7%0%3%0% Neutropenia0% 7%0% Hypertension8%1%8%0% Proteinuria3%0%5%0% Venous thrombosis0% 1%4% Bleeding9%0%8%0% Maximum Per Patient Toxicities during MAINTENANCE TX Maximum Per Patient Toxicities during MAINTENANCE TX

25 ConclusionsConclusions The study is still ongoing Accrual updated at May 31 st 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 Ancona S. Cascinu, M. Scartozzi, R. Berardi Monza P. Bidoli, R. Longarini, D. Cortinovis Arezzo S. Bracarda, M. Sisani, S. Del Buono Napoli – Federico II ° G. Tortora, C. Carlomagno, A. De Stefano Aviano S. Frustaci, A. Buonadonna, G. Tabaro Padova S. Lonardi, A. Cappetta Brescia A. Zaniboni, M. Mazzocchi Parma A. Ardizzoni, R. Camisa, E. Rapacchi, F. Pucci, F. Leonardi Caltanissetta S. Vitello, C. Raimondi Pisa A. Falcone, G. Masi, F. Loupakis, E. Vasile, I. Brunetti Cremona R. Passalacqua, M. Dalla Chiesa, G. Tomasello, S. Lazzarelli Pistoia M. Di Lieto Cuneo M. Merlano, C. Granetto, M. Gasco Pontedera G. Allegrini, L. Marcucci, S. Lucchesi Firenze L. Fioretto, A. Ribecco, F. Martella Prato A. Di Leo, A. Ciarlo, F. Del Monte Genova Galliera A. De Censi Reggio Emilia C. Boni, M. Banzi, R. Gnoni Genova IST S. Chiara, C. Sonaglio, D. Garbarino Roma CBM G. Tonini, D. Santini, B. Vincenzi, O. Venditti Lecce V. Lo Russo, L. Petrucelli Roma - Gemelli C. Barone, Dr. P. Di Nardo, Dr. A. Inno, Dr. A. Amoruso Livorno F. Cappuzzo, S. Cupini, Dr. C. Barbara, V. Safina, A. Antonuzzo Roma - Umberto I° E. Cortesi, A. Tuzi, P. Trenta, A. Pellegrino, M. Mazzoli Milano HSR E. Villa, M. Ronzoni, V. Ricci Sondrio A. Bertolini, E. Menatti Milano Niguarda S. Siena, A. Sartore-Bianchi, K. Bencardino, Y. Franzosi Torino L. Ciuffreda, P. Racca, C. Bonfadini, C. Taverniti Mirano O. Vinante, B. Silvestri Viareggio D. Amoroso, C. Valsuani, M. Ricasoli, C. Puccetti


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