ASCO - Gastrointestinal Cancers Symposium

Orlando (FL), 25-27 January 2008

First-line Irinotecan, Oxaliplatin and Infusional 5FU/LV (FOLFOXIRI) in combination with Bevacizumab (BV) in Metastatic Colorectal Cancer (mCRC) Patients (pts): a

Phase II Study by the G.O.N.O. Group

Masi G1, Loupakis F1,6, Baldi G1, Fornaro L1, Di Leo A2, Ciarlo A2, Amoroso D3, Granetto C4, Di Donato S5, Falcone A1,6.

1Division of Medical Oncology, Azienda USL 6 - Istituto Toscano Tumori Livorno, Italy, 2Division of Medical Oncology, Misericordia e Dolce Hospital, Prato, Italy,

3Division of Medical Oncology, Versilia Hospital, Lido di Camaiore, Italy,4Division of Medical Oncology, S. Croce e Carle Hospital, Cuneo, Italy,

5Division of Medical Oncology, S. Chiara Hospital, Pisa, Italy,6Department of Oncology, Transplantation and New Technologies in Medicine,

University of Pisa, Italy

ABSTRACT (updated)ABSTRACT (updated)

Background: A phase III study demonstrated that the GONO-FOLFOXIRI regimen significantly improved response-rate (RR), progression-free survival (PFS), overall survival (OS) and post-CT surgical resections of metastases vs FOLFIRI. The combination of BV with fluoropyrimidines/oxaliplatin/irinotecan-based doublets is safe and associated with promising activity and efficacy.

Methods: We are conducting a phase II study to evaluate the bi-weekly combination of bevacizumab 5 mg/kg on d1 with the GONO-FOLFOXIRI regimen (irinotecan 165 mg/sqm d1, oxaliplatin 85 mg/sqm d1, l-LV 200 mg/sqm d1 and 5FU 3200 mg/sqm 48-h flat continuous infusion starting on d1) (FOIB regimen) in initially unresectable mCRC pts.

Results: Up today 40 pts have been enrolled. Main pts characteristic are: M/F = 65%/35%, median age (range) = 61 (41-75) years, ECOG-PS 0/1 = 68%/32%, primary colon/rectum = 72%/28%, primary on site = 10 pts (25%), sites of disease single/multiple = 52%/48%, liver only mts = 50%. Among the 38 pts so far assessable for toxicity the G3-4 maximum observed toxicities were: neutropenia 34% (febrile neutropenia 3%), diarrhea 8%, nausea 5%, stomatitis 3%, neurotoxicity 3%, deep venous thrombosis 5% and hypertension 8%; G1 bleeding occurred in 12 pts (32%). No toxic deaths have occurred. Up today 29 pts have been evaluated for response and we observed 2 CR, 20 PR (ORR = 76%) and 7 SD (disease control rate = 100%). So far 5 pts (17%) have undergone to secondary surgery on liver mts and 4 R0 resections have been performed. After a median follow up of 6.5 months, median PFS and OS have not yet been reached.

Conclusions: The addiction of BV to the GONO-FOLFOXIRI regimen is feasible with manageable toxicities; the characteristic toxicity of BV and FOLFOXIRI occurs with the expected incidence and there were not unexpected adverse events. Preliminary data on activity are promising. The study is still ongoing. Partially supported by ARCO Foundation.

BACKGROUNDBACKGROUND

The best outcome of mCRC is achieved in pts receiving 5FU, irinotecan, and oxaliplatin in the course of their disease, but in a sequential strategy 25-50% of pts does not receive II line CT and therefore is not exposed to all the 3 agents. A way to expose 100% of pts to all the 3 agents is to incorporate them in first-line therapy.

The “GONO” FOLFOXIRI regimen is the first triple-drug combination demonstrated to be superior to an infusional 5FU containing doublet as FOLFIRI in terms of RR, R0 resections, PFS and OS in metastatic colorectal cancer patients (Falcone A, J Clin Oncol 2007).

Bevacizumab associated with IFL is feasible and significantly improves response rate, progression free and overall survival compared to IFL alone in first-line treatment of MCRC pts.

Bevacizumab associated with oxaliplatin-based chemotherapy (FOLFOX or XELOX) is feasible and significantly increases progression free survival compared to chemotherapy alone in first- and second-line treatment of MCRC pts.

Two large phase IV trials evaluating a total of about 4000 MCRC pts show that the combination of Bevacizumab with any first-line chemotherapy is safe and effective.

OBJECTIVESOBJECTIVES

PRIMARY

Percentage of patients free of progression at 10 months

SECONDARY

Response rate

Progression free survival

Overall survival

Safety profile

Evaluation of potential surrogate markers predictive of

bevacizumab activity

SELECTION CRITERIASELECTION CRITERIAINCLUSION CRITERIA

Histologically confirmed colorectal adenocarcinoma Unresectable and measurable metastatic disease (RECIST criteria) Age > 18 years and ≤ 75 years ECOG PS < 2 if aged < 71 years; ECOG PS = 0 if aged 71-75 years Previous adjuvant chemotherapy allowed if more than 12 months have elapsed between the end of adjuvant therapy and first relapse Adeguate liver, renal and bone marrow functions Urine dipstick for proteinuria < 2+

EXCLUSION CRITERIA

Prior palliative chemotherapy of bevacizumab treatment Bowel obstruction, inflammatory enteropathy, extensive intestinal resection Presence or history of CNS metastasis Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to treatment Clinically significant cardiovascular disease, uncontrolled hypertension, thromboembolic or hemorrhagic events within 6 months prior to treatment, bleeding diathesis or coagulopathy

TREATMENTTREATMENT

So far, 289 cycles of “induction” treatment with FOLFOXIRI plus Bevacizumab were administered and the median number of cycles FOLFOXIRI plus Bevacizumab was 8 (range 1-16)

5FU flat continuous infusion3200 mg/sqm

L-LV 200 mg/sqm

Oxaliplatin 85 mg/sqm

2 hoursRepeated every 14 days

CPT-11165 mg/sqm

48 hours

Day 1 Day 2 Day 3

1 hour

BV5 mg/Kg

30 min

PATIENTS’ CHARACTERISTICSPATIENTS’ CHARACTERISTICS

N %

Patients 40 -

Age, median (range) 60 (41-75) -

Sex (M/F) 26/14 65/35

ECOG PS 0/1 27/13 67.5/32.5

Primary site (colon/rectum) 29/11 72.5/27.5

Surgery for primary tumor (y/n) 30/10 75/25

Previous adjuvant CT (y/n) 2/38 5/95Sites of disease (single/multiple)

21/19 52.5/47.5

Liver only mts 20 50

Lung only mts 1 2.5

TOXICITY (% per cycle; N=289)TOXICITY (% per cycle; N=289)

Toxicity G1 G2 G3 G4

Nausea 24 8 1 0

Vomiting 7 5 0 0

Diarrhea 22 7 1 0

Stomatitis 27 3 1 0

Neutropenia 12 9 6 2

Thrombocytopenia 14 0 0 0

Anemia 41 11 1 0

Neurotoxicity 40 17 1 0

Hypertension 3 1 2 0

Deep venous thrombosis 0 0 1 0

Bleeding 6 0 0 0

Cardiac ischemia 0 0 1 0

Febrile neutropenia 1%. No toxic death has so far occurred.

TOXICITY (% per patient; N=38)TOXICITY (% per patient; N=38)

Toxicity G1 G2 G3 G4

Nausea 42 18 5 0

Vomiting 24 21 0 0

Diarrhea 24 24 8 0

Stomatitis 42 13 3 0

Neutropenia 18 13 21 13

Thrombocytopenia 26 0 0 0

Anemia 42 24 5 0

Neurotoxicity 34 24 3 0

Hypertension 18 3 8 0

Deep venous thrombosis 0 0 5 0

Bleeding 32 0 0 0

Cardiac ischemia 0 0 5 0

Febrile neutropenia 3% (1 patient). No toxic death has so far occurred.

RESPONSE RATE (RECIST CRITERIA)RESPONSE RATE (RECIST CRITERIA)

Total evaluable patients N=29

Complete Response (CR) 2 7%

Partial Response (PR) 20 69%

Overall Response Rate 22 76%

Stable Disease (SD) 7 24%

Progressive Disease 0 0

Disease Control Rate

(CR + PR + SD)29 100%

R0-SURGERY, PFS, OSR0-SURGERY, PFS, OS

So far 5 pts (17%) have undergone to secondary

surgery on liver mts; 4 R0 and 1 R1 resections have

been performed

After a median follow up of 6.5 months, median PFS

and OS have not yet been reached

CONCLUSIONSCONCLUSIONS

The addiction of BV to the GONO-FOLFOXIRI regimen is

feasible with manageable toxicities

The characteristic toxicity of BV and FOLFOXIRI occurs

with the expected incidence and there were not unexpected

adverse events

Preliminary data on activity are promising.

The study is still ongoing to complete the planned accrual

and to better determine the activity and safety profile of the

combination.

ACKNOWLEDGEMENTSACKNOWLEDGEMENTS

LivornoMasi G, Loupakis F, Baldi G, Fornaro L, Antonuzzo A, Di Marsico R, Stasi I, Cupini S, Fontana A, Vasile E, Andreuccetti M, Falcone A.

Prato Ciarlo A, Cavaciocchi D, Di Leo A.

Versilia Donati S, Rondini M, Puccetti C, Amoroso D.

Cuneo Granetto C, Fea E, Merlano M.

Pisa Di Donato S, Brunetti I, Lencioni M, Pfanner E, Petrini I, Ricci S.

Genova Sonaglio C, Chiara S.

Roma Ferraldeschi R, Puglisi M, Cortesi E.