American Society of Clinical Oncology Annual Meeting 2010
Chicago, Illinois - June 04-08, 2010
FOLFOXIRI plus bevacizumab (BV) vs FOLFIRI plus BV as firstline 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 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
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 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
Study Design
Stratification
• Center
• PS 0 vs 1-2
• Adjuvant CT
R
A
N
D
O
M
FOLFIRI + BV
5-FU + BV
FOLFOXIRI + BV
5-FU + BV
INDUCTION TX
MAINTENANCE TX
• up to 12 cycles
• until PD
• or PD
• or intolerable toxicity
• or unacceptable
• or patient’s refusal
toxicity
• or patient’s refusal
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
Repeated every 2 weeks
48 hours
FOLFIRI + BEVACIZUMAB: INDUCTION SCHEDULE
Day 1
Day 2
& Day 3
BV
5 mg/Kg
CPT-11
180 mg/sqm
L-LV
200 mg/sqm
30 min
90 min
5FU bolus
5FU flat continuous infusion
400 mg/sqm
2400 mg/sqm
bolus
Repeated every 2 weeks
48 hours
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
Maintenance Treatment: Schedules
INDUCTION TX
MAINTENANCE TX
5-FU/LV + BV
FOLFIRI + BV
BV
5 mg/kg 30-min d.1
L-LV
200 mg/m2 2-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
5-FU/LV + BV
FOLFOXIRI + 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
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
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
Main exclusion criteria
•
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
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.
Dose Reductions and Delays Criteria: Chemotherapy
AT THE START OF CYCLE
GRADE
WBC
< 3.000/mm3
Neutrophils
< 1.000/mm3
CPT-11
LOHP
5-FU
Platelets
< 100.000/mm3
Diarrhea
≥1
Mucositis
≥1
Any other NHT
≥2
HFS
3-4
100%
100%
STOP
Neurotoxicity
≥3
100%
STOP
100%
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%
PREVIOUS TOXICITY
HOLD UNTIL RESOLUTION
Dose 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 Analysis
 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 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 graded according to NCI-CTC
version 3.0.
Patients Characteristics
FOLFIRI + BV
74 pts
FOLFOXIRI + BV
76 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%
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
N. of induction treatment
cycles administered
Median N. of induction
treatment cycles per patient
7% / 91%
3% / 93%
714
724
12
11
Primary on site
Maximum Per Patient Non-Haematological Toxicities
during INDUCTION TX
FOLFIRI + BV
74 pts
FOLFOXIRI + BV
76 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 Haematological Toxicities
during INDUCTION TX
FOLFIRI + BV
74 pts
FOLFOXIRI + BV
76 pts
G1-2
G3-4
G1-2
G3-4
24%
14%
22%
47%
Febrile Neutropenia
-
4%
-
7%
Thrombocytopenia
8%
1%
22%
3%
Anemia
51%
0%
62%
1%
Neutropenia
Maximum Per Patient Cardiovascular Toxicities
during INDUCTION TX
FOLFIRI + BV
74 pts
FOLFOXIRI + BV
76 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 Cycle Toxicities
during INDUCTION TX
FOLFIRI + BV
74 pts
FOLFOXIRI + BV
76 pts
714
724
N. of cycles administered
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%
Serious Adverse Events (during INDUCTION Treatment)
FOLFIRI
74 pts
All SAE
Type of
Serious
Adverse
Events
11 pts
(15%)
FOLFOXIRI
76 pts
15 pts
(20%)
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)
* based on investigators’ judgment
FOLFIRI
74 pts
Possibly
Treatment
Related
Deaths*
3 pts
(4%)
FOLFOXIRI
76 pts
2 pts
(3%)
1 Stroke
1 GI bleeding
2 Pulmonary Embolism
1 Sepsis
Dose Reductions and Treatment Delays due to
Toxicities during INDUCTION TX
FOLFIRI + BV
74 pts
FOLFOXIRI + BV
76 pts
• 5-Fluorouracil
5%
6%
• Irinotecan
5%
9%
• Oxaliplatin
NA
9%
• 5-Fluorouracil
5%
21%
• Irinotecan
5%
21%
• Oxaliplatin
NA
21%
• BV
0%
12%
DOSE REDUCTIONS
TREATMENT DELAYS
Supportive Therapies during INDUCTION TX
FOLFIRI + BV FOLFOXIRI + BV
74 pts
76 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
Maximum Per Patient Toxicities
during MAINTENANCE TX
FOLFIRI + BV
74 pts
FOLFOXIRI + BV
76 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%
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
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
Caltanissetta
S. Vitello, C. Raimondi
Pisa
A. Ardizzoni,
R. Camisa, E.
Rapacchi, F. Pucci, F. Leonardi
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
Lecce
V. Lo Russo, L. Petrucelli
Roma - Gemelli
Livorno
F. Cappuzzo, S. Cupini, Dr. C. Barbara,
V. Safina, A. Antonuzzo
Roma - Umberto I°
G. Tonini, D. Santini, B. Vincenzi, O.
Venditti
C. Barone, Dr. P. Di Nardo, Dr. A.
Inno, Dr. A. Amoruso
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,
Bencardino, Y. Franzosi
Mirano
O. Vinante, B. Silvestri
K.
Torino
Viareggio
L. Ciuffreda, P. Racca, C. Bonfadini,
C. Taverniti
D. Amoroso, C. Valsuani, M.
Ricasoli, C. Puccetti