FOLFOXIRI plus bevacizumab (BV) vs FOLFIRI plus BV as first-FOLFOXIRI plus bevacizumab (BV) vs FOLFIRI plus BV as first-line treatment of metastatic colorectal cancer (MCRC): line treatment of metastatic colorectal cancer (MCRC): preliminary safety results of the phase III randomized preliminary safety results of the phase III randomized “TRIBE” study by the Gruppo Oncologico Nord-Ovest “TRIBE” study by the Gruppo Oncologico Nord-Ovest
(GONO).(GONO).
Alfredo Falcone 1,2, Fotios Loupakis 1,2, 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
American Society of Clinical Oncology Annual Meeting 2010Chicago, Illinois - June 04-08, 2010
RationaleRationale
The combination of BV with cytotoxic drugs is an efficacious strategy in the treatment of mCRC.
Hurwitz H, N Eng J Med 2004Giantonio B, J Clin oncol 2007Saltz 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
Study DesignStudy Design
FOLFIRI + BVFOLFIRI + BV
FOLFOXIRI + BVFOLFOXIRI + BV
Stratification• Center• PS 0 vs 1-2• Adjuvant CT
RRAANNDDOOMM
5-FU + BV5-FU + BV
5-FU + BV5-FU + BV
INDUCTION TXINDUCTION TX• up to 12 cycles• or PD• or unacceptable
toxicity• or patient’s refusal
MAINTENANCE TXMAINTENANCE TX• until PD• or intolerable toxicity• or patient’s refusal
5FU flat continuous infusion5FU flat continuous infusion3200 mg/sqm3200 mg/sqm
L-LV L-LV 200 mg/sqm200 mg/sqm
Oxaliplatin Oxaliplatin 85 mg/sqm85 mg/sqm
2 hours2 hours
Repeated every 2 weeks
CPT-11CPT-11165 mg/sqm165 mg/sqm
48 hours48 hours
Day 1 Day 2 & Day 3
1 hour1 hour
BVBV5 mg/Kg5 mg/Kg
30 min30 min
FOLFOXIRI + BEVACIZUMAB: INDUCTION SCHEDULEFOLFOXIRI + BEVACIZUMAB: INDUCTION SCHEDULE
5FU flat continuous infusion2400 mg/sqm
5FU bolus5FU bolus400 mg/sqm400 mg/sqm
bolusbolus
Repeated every 2 weeks
CPT-11CPT-11180 mg/sqm180 mg/sqm
48 hours48 hours
Day 1 Day 2 & Day 3
90 min90 min
BVBV5 mg/Kg5 mg/Kg
30 min30 min
FOLFIRI + BEVACIZUMAB: INDUCTION SCHEDULEFOLFIRI + BEVACIZUMAB: INDUCTION SCHEDULE
L-LV L-LV 200 mg/sqm200 mg/sqm
5FU flat continuous infusion2400 - 3200 mg/sqm
Repeated every 2 weeks
48 hours48 hours
Day 1 Day 2 & Day 3
90 min90 min
BVBV5 mg/Kg5 mg/Kg
30 min30 min
5FU/LV + BEVACIZUMAB: MAINTENANCE SCHEDULE5FU/LV + BEVACIZUMAB: MAINTENANCE SCHEDULE
L-LV L-LV 200 mg/sqm200 mg/sqm
FOLFIRI + BVFOLFIRI + BV
FOLFOXIRI + BVFOLFOXIRI + BV
Maintenance Treatment: SchedulesMaintenance Treatment: Schedules
5-FU/LV + BV5-FU/LV + BVBV 5 mg/kg 30-min d.1L-LV 200 mg/m2 2-h d.15FU 400 mg/m2 bolus d.15FU 2400 mg/m2 46-h CI d.1q. 2 wks x 12 cycles
5-FU/LV + BV5-FU/LV + BVBV 5 mg/kg 30-min d.1L-LV 200 mg/m2 2-h d.15FU 3200 mg/m2 48-h CI d.1q. 2 wks x 12 cycles
INDUCTION TXINDUCTION TX MAINTENANCE TXMAINTENANCE TX
Study ObjectivesStudy Objectives
PRIMARYPRIMARY Progression free survival
SECONDARYSECONDARY Overall response rate Duration of response R0 surgery of metastases Overall survival Safety profile Potential markers predictive of bevacizumab activity
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 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
• 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
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 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.
Dose Reductions and Delays Criteria: ChemotherapyDose Reductions and Delays Criteria: Chemotherapy
AT THE START OF CYCLE GRADE CPT-11 LOHP 5-FU
WBC < 3.000/mm3
HOLD UNTIL RESOLUTION
Neutrophils < 1.000/mm3
Platelets < 100.000/mm3
Diarrhea ≥ 1
Mucositis ≥ 1
Any other NHT ≥ 2
HFS 3-4 100% 100% STOP
Neurotoxicity ≥ 3 100% STOP 100%
PREVIOUS TOXICITY GRADE CPT-11 LOHP 5-FU
Febrile neutropenia 4 75% 75% 100%
Thrombocytopenia 3-4 75% 75% 100%
Diarrhea 3 75% 100% 75%
Diarrhea 4 50% 100% 50%
Mucositis 3 100% 100% 75%
Mucositis 4 100% 100% 50%
Dose Reductions and Delays Criteria: BevacizumabDose Reductions and Delays Criteria: Bevacizumab
TOXICITY GRADE BV
Hypertension 3 STOP if uncontrolled despite appropriate tx
Hypertension 4 STOP
Hemorrhage 2-3 HOLD UNTIL RESOLUTION
Hemorrhage 4 STOP
Venous thrombosis 3-4 STOP
Arterial thrombosis Any STOP
Congestive heart failure 3 HOLD UNTIL GRADE ≤2
Congestive heart failure 4 STOP
Proteinuria 3 HOLD UNTIL GRADE ≤2
Proteinuria 4 STOP
GI perforation Any STOP
Wound dehiscence Any STOP
Safety Interim AnalysisSafety Interim Analysis
At the time of the present analysis, 268 patients have 268 patients have been enrolledbeen enrolled into the study:
Arm A: FOLFIRI + BV: 133Arm A: FOLFIRI + BV: 133
Arm B: FOLFOXIRI + BV: 135Arm B: FOLFOXIRI + BV: 135 The objective of this interim analysis is to evaluate
safety among the first 150 patients enrolledthe first 150 patients enrolled:
Arm A: FOLFIRI + BV: 74Arm A: FOLFIRI + BV: 74
Arm B: FOLFOXIRI + BV: 76Arm B: FOLFOXIRI + BV: 76 All toxic events are graded according to NCI-CTC NCI-CTC
version 3.0version 3.0.
FOLFIRI + BV74 pts
FOLFOXIRI + BV76 pts
Age, median (range) 59 (29-74) 58 (29-74)
Sex M/F 51% / 49% 59% / 41%
ECOG PS 0/1-2 89% / 11% 87% / 13%
Primary Colon/Rectum 69% / 31% 72% / 28%
Primary on site 26% 22%
Sites of mts 1/≥2 23%/77% 34% /66%
Previous adjuvant CT Y/N 11% / 89% 11% / 89%
Previous adjuvant RT Y/N 7% / 91% 3% / 93%N. of induction treatment cycles administered 714 724
Median N. of induction treatment cycles per patient 12 11
Patients CharacteristicsPatients Characteristics
FOLFIRI + BV74 pts
FOLFOXIRI + BV76 pts
G1-2 G3-4 G1-2 G3-4
Nausea 57% 1% 51% 4%
Vomiting 20% 0% 30% 5%
Diarrhea 46% 8% 50% 20%
Stomatitis 39% 5% 45% 9%
Asthenia 46% 8% 59% 7%
Hand-Foot Syndrome 11% 0% 12% 0%
Neurotoxicity (grade 2-3) NA 22%
Maximum Per Patient Non-Haematological ToxicitiesMaximum Per Patient Non-Haematological Toxicitiesduring INDUCTION TXduring INDUCTION TX
FOLFIRI + BV74 pts
FOLFOXIRI + BV76 pts
G1-2 G3-4 G1-2 G3-4
Neutropenia 24% 14% 22% 47%
Febrile Neutropenia - 4% - 7%
Thrombocytopenia 8% 1% 22% 3%
Anemia 51% 0% 62% 1%
Maximum Per Patient Haematological ToxicitiesMaximum Per Patient Haematological Toxicitiesduring INDUCTION TXduring INDUCTION TX
FOLFIRI + BV74 pts
FOLFOXIRI + BV76 pts
G1-2 G3-4 G1-2 G3-4
Hypertension 22% 1% 17% 1%
Bleeding 27% 0% 29% 3%
Venous thrombosis 0% 8% 3% 9%
Arterial thrombosis 0% 1% 0% 3%
GI perforation 0% 0% 0% 1%
Proteinuria 19% 1% 22% 1%
Ematuria 8% 1% 9% 0%
Maximum Per Patient Cardiovascular ToxicitiesMaximum Per Patient Cardiovascular Toxicitiesduring INDUCTION TXduring INDUCTION TX
FOLFIRI + BV74 pts
FOLFOXIRI + BV76 pts
N. of cycles administered 714 724
G1-2 G3-4 G1-2 G3-4
Diarrhea 22% 1% 26% 3%
Stomatitis 13% 1% 14% 1%
Neutropenia 10% 3% 22% 11%
Febrile Neutropenia - 1% - 1%
Thrombocytopenia 3% 1% 8% 1%
Maximum Per Cycle ToxicitiesMaximum Per Cycle Toxicitiesduring INDUCTION TXduring INDUCTION TX
Serious Adverse Events (during INDUCTION Treatment)Serious Adverse Events (during INDUCTION Treatment)
FOLFIRI74 pts
FOLFOXIRI76 pts
All SAE 11 pts (15%) 15 pts (20%)
Type of Serious Adverse Events
1 Stroke 1 Cardiac Ischemia
1 Sudden Death 2 Atrial Flutter
2 Pulmonary Embolism 1 Sepsis
1 Deep Vein Thrombosis 1 Pneumonia
1 GI Bleeding 1 GI Bleeding
1 GI Obstruction 1 GI Perforation
3 Diarrhea 6 Diarrhea
1 Febrile Neutropenia 2 Febrile Neutropenia
Possibly Tx-related Deaths (during INDUCTION Treatment)Possibly Tx-related Deaths (during INDUCTION Treatment)Possibly Tx-related Deaths (during INDUCTION Treatment)Possibly Tx-related Deaths (during INDUCTION Treatment)
FOLFIRI74 pts
FOLFOXIRI76 pts
PossiblyTreatment
RelatedDeaths*
3 pts (4%) 2 pts (3%)
1 Stroke 1 GI bleeding
2 Pulmonary Embolism 1 Sepsis
* based on investigators’ judgment
FOLFIRI + BV74 pts
FOLFOXIRI + BV76 pts
DOSE REDUCTIONS• 5-Fluorouracil 5% 6%• Irinotecan 5% 9%• Oxaliplatin NA 9%
TREATMENT DELAYS• 5-Fluorouracil 5% 21%• Irinotecan 5% 21%• Oxaliplatin NA 21%• BV 0% 12%
Dose Reductions and Treatment Delays due to Dose Reductions and Treatment Delays due to Toxicities during INDUCTION TXToxicities during INDUCTION TX
Supportive Therapies during INDUCTION TXSupportive Therapies during INDUCTION TX
FOLFIRI + BV74 pts
FOLFOXIRI + BV76 pts
G-CSF* 15% 26%
ESA** 3% 7%
LMWH*** 11% 8%
Oral Anticoagulant 0% 0%
*G-CSF, Granulocyte-Colony Stimulating Factor**ESA, Erithropoiesis-Stimulating Agents***LMWH, Low Molecular Weight Heparin
FOLFIRI + BV74 pts
FOLFOXIRI + BV76 pts
G1-2 G3-4 G1-2 G3-4
Vomiting 9% 0% 1% 0%
Diarrhea 9% 0% 7% 0%
Stomatitis 11% 0% 11% 0%
Hand-Foot Syndrome 7% 0% 3% 0%
Neutropenia 0% 0% 7% 0%
Hypertension 8% 1% 8% 0%
Proteinuria 3% 0% 5% 0%
Venous thrombosis 0% 0% 1% 4%
Bleeding 9% 0% 8% 0%
Maximum Per Patient ToxicitiesMaximum Per Patient Toxicitiesduring MAINTENANCE TXduring MAINTENANCE TX
ConclusionsConclusionsConclusionsConclusions
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
Enrolling CentersEnrolling CentersEnrolling CentersEnrolling CentersAncona 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 ParmaA. Ardizzoni, R. Camisa, E. Rapacchi, F. Pucci, F. Leonardi
Caltanissetta S. Vitello, C. Raimondi PisaA. Falcone, G. Masi, F. Loupakis, E. Vasile, I. Brunetti
CremonaR. 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 CBMG. Tonini, D. Santini, B. Vincenzi, O. Venditti
Lecce V. Lo Russo, L. Petrucelli Roma - GemelliC. Barone, Dr. P. Di Nardo, Dr. A. Inno, Dr. A. Amoruso
LivornoF. 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 NiguardaS. Siena, A. Sartore-Bianchi, K. Bencardino, Y. Franzosi Torino
L. Ciuffreda, P. Racca, C. Bonfadini, C. Taverniti
Mirano O. Vinante, B. Silvestri ViareggioD. Amoroso, C. Valsuani, M. Ricasoli, C. Puccetti