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).*TRIBE = TRIPLET + BEVACIZUMAB

1,2 1,2 3 4 5 6 7 8Alfredo Falcone , Fotios Loupakis , Samanta Cupini , Enrico Cortesi , Angela Buonadonna , Gianluca Tomasello , Maria Banzi , Monica Ronzoni , 9 1,2

Alberto Zaniboni , Gianluca Masi .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

ABSTR. ID

3543

GONO

RUPPO

NCOLOGICO

ORD

VEST

Rationale

v 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

v The triple drug combination FOLFOXIRI demonstrated

increased activity and efficacy over FOLFIRI in a

randomized trial.

Falcone A, J Clin Oncol 2007

v The combination of FOLFOXIRI plus BV demonstrated

promising results in phase II.

Masi G, ESMO 2009

Study Design

FOLFIRI + BV

FOLFOXIRI + BV

Stratification

• Center

• PS 0 vs 1-2

• Adjuvant CT

RANDOM

5-FU + 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

5FU flat continuous infusion3200 mg/sqm

L-LV 200 mg/sqm

Oxaliplatin 85 mg/sqm

2 hours

Repeated every 2 weeks

CPT-11165 mg/sqm

48 hours

Day 1 Day 2 & Day 3

1 hour

BV5 mg/Kg

30 min

FOLFOXIRI + BEVACIZUMAB: INDUCTION SCHEDULE

5FU flat continuous infusion2400 mg/sqm

5FU bolus400 mg/sqm

bolus

Repeated every 2 weeks

CPT-11180 mg/sqm

48 hours

Day 1 Day 2 & Day 3

90 min

BV5 mg/Kg

30 min

FOLFIRI + BEVACIZUMAB: INDUCTION SCHEDULE

L-LV 200 mg/sqm

FOLFIRI + BV

FOLFOXIRI + BV

Maintenance Treatment: Schedules

5-FU/LV + BVBV 5 mg/kg 30-min d.1L-LV 200 mg/m2 2-h d.1

5FU 400 mg/m2 bolus d.15FU 2400 mg/m2 46-h CI d.1q. 2 wks x 12 cycles

5-FU/LV + BVBV 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

INDUCTION TX MAINTENANCE TX

Study Objectives

èPRIMARY

ü Progression free survival

èSECONDARY

ü Overall response rate

ü Duration of response

ü R0 surgery of metastases

ü Overall survival

ü Safety profile

ü 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 (cerebrovascularaccidents =6 months, myocardial infarction = 6 months, unstableangina, NYHA grade II or greater congestive heart failure, seriouscardiac arrhythmia requiring medication).

• Uncontrolled hypertension

• Treatment with anticoagulants for therapeutic purposes

• Major surgical procedure, open biopsy, or significant traumaticinjury within 28 days prior to study treatment start

• Lack of physical integrity of the upper gastrointestinal tract,malabsorption syndrome

Main exclusion criteria Statistics

ü The primary study end-point is Progression Free Survival

ü 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.

ü 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.

ü 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.

ü 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 CPT-11 LOHP 5-FU

WBC < 3.000/mm3

HOLD UNTIL RESOLUTION

Neutrophils < 1.000/mm3

Platelets < 100.000/mm3

Diarrhea = 1

Mucosit is = 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%

Mucosit is 3 100% 100% 75%

Mucosit is 4 100% 100% 50%

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

v 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

v 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

v All toxic events are graded according to NCI-CTC

version 3.0.

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%

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 Characteristics

FOLFIRI + BV

74 pts

FOLFOXIRI + BV

76 ptsG1-2 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 Toxicitiesduring INDUCTION TX

FOLFIRI + BV

74 pts

FOLFOXIRI + BV

76 ptsG1-2 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 Toxicitiesduring INDUCTION TX

FOLFIRI + BV

74 pts

FOLFOXIRI + BV

76 ptsG1-2 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 Toxicitiesduring INDUCTION TX

FOLFIRI + BV

74 pts

FOLFOXIRI + BV

76 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 Toxicitiesduring INDUCTION TX

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 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

FOLFIRI + BV

74 pts

FOLFOXIRI + BV

76 ptsDOSE 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 Toxicities during INDUCTION TX

Supportive Therapies during INDUCTION TX

FOLFIRI + BV

74 pts

FOLFOXIRI + BV

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

FOLFIRI + BV

74 pts

FOLFOXIRI + BV

76 ptsG1-2 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 Toxicitiesduring MAINTENANCE TX

Conclusions

üThe study is still ongoing

üAccrual updated at May 31st 2010 is 272

patients

üThese preliminary results demonstrate that

both treatment arms are safe and feasible

üThe side-effects occur with the expected

incidence and there were not unexpected

toxicities

Enrolling Centers

Ancona S. Cascinu , M. Scar tozzi , R. Berardi Monza P. Bidoli , R. Longarini, D. Cortin ovis

Arezzo S. Bracarda, M . Sisan i, S. Del Buono Napoli – Federico II°G. Tortora, C. Car lomagn o, A. DeStefano

Aviano S. Frustaci, A. Buon adonna, G. Tabar o Padova S. Lonardi, A. Cappetta

Brescia A. Zanibon i, M . Mazzocchi Parma A. Ar dizzoni, R. Camisa, E.Rapacchi, F. Pucci, F. Leonardi

Caltanissetta S. Vitello, C. Raimondi Pisa A. Fa lcone, G. Ma si, F. Loupa kis, E.Vasile, I. Brunetti

CremonaR. Passalacqu a, M. Dalla Chiesa, G.Tomasello, S. Lazzarell i Pistoia M . Di Lieto

Cuneo M. M erlano, C . Gr anetto, M. Gasco Pontedera G. Allegrini, L. Marcucci, S. Lu cch esi

Firenze L. Fioretto, A. Ribecco, F. Martella Prato A. Di Leo, A. Ciar lo, F. Del Mon te

Genova Galliera A. De Censi Reggio Emilia C. Boni, M . Banzi, R . Gn oni

Genova IST S. Chia ra, C. Sonaglio, D. Garbarino Roma CBMG. Ton ini, D. Santini, B . Vincenzi, O.Venditti

Lecce V. Lo Russo, L. Petrucell i Roma - GemelliC. Bar one, Dr. P. Di Na rdo, Dr. A.

Inno, Dr. A. Amoruso

LivornoF. Cappu zzo, S. Cupini, Dr. C. Barbara,V. Safina, A. Anton uzzo Roma - Umberto I°

E. Cortes i, A. Tuz i, P. Tr enta, A.Pellegr ino, M. Mazzoli

Milano HSR E. Villa, M. Ro nzoni, V. Ricci Sondrio A. Bertolini , E. Mena tti

Milano NiguardaS. Siena, A. Sa rtore-Bianchi, K.Ben cardino, Y. Fr anzos i Torino

L. Ciuffreda , P. Racca, C. Bo nfadin i,C. Taverniti

Mirano O. Vinante, B. Silvestri ViareggioD. Amoroso, C. Valsuani, M.

Ricasoli, C. P uccetti

Possibly Tx-related Deaths (during INDUCTION Treatment)

FOLFIRI

74 pts

FOLFOXIRI

76 pts

Possibly

Treatment

Related

Deaths*

3 pts (4%) 2 pts (3%)

1 Stroke 1 GI bleeding

2 Pulmonary Embolism 1 Sepsis

* based on investigators’ judgment