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