ASCO 2008 Annual MeetingChicago (IL), May 30 – June 3, 2008

FOLFOXIRI (irinotecan, oxaliplatin and infusional 5FU/LV) in combination with bevacizumab (BV) in the

first-line treatment of metastatic colorectal cancer (mCRC): a phase II study by the G.O.N.O. group

A. Falcone1,2, G. Masi 2, F. Loupakis 1,2, E. Vasile1,2, A. Ciarlo3, D. Cavaciocchi 3, D. Amoroso 4, M. Puglisi 5, E. Fea 6, I. Brunetti 7

1Department of Oncology, Transplantation and New Technologies in Medicine, University of Pisa, Italy2Division of Medical Oncology, Azienda USL 6 - Istituto Toscano Tumori Livorno, Italy,

3Division of Medical Oncology, Misericordia e Dolce Hospital, Prato, Italy, 4Division of Medical Oncology, Versilia Hospital, Lido di Camaiore, Italy,

5Division of Medical Oncology, University “La Sapienza”, Rome, Italy6Division of Medical Oncology, S. Croce e Carle Hospital, Cuneo, Italy,

7Division of Medical Oncology, S. Chiara Hospital, Pisa, Italy

Abstract n. 33736

ABSTRACT (updated)

Background: The GONO-FOLFOXIRI regimen significantly improved response-rate (RR), progression-free survival (PFS), overall survival (OS) and post-CT surgical resection of metastases compared to FOLFIRI in a phase III study. The combination of BV with fluoropyrimidines/oxaliplatin/irinotecan-based doublets is safe and associated with improved efficacy.

Methods: This phase II trial evaluates the 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) repeated every 2 weeks, as first-line treatment of initially unresectable mCRC pts.

Results: Fifty-seven pts have been enrolled. Main pts characteristic are: M/F = 60%/40%, median age (range) = 61 (34-75) years, ECOG-PS 0/1/2 = 69%/26%/5%, primary colon/rectum = 72%/28%, primary on site = 13 pts (23%), sites of disease single/multiple = 56%/44%, liver only mts = 53%. All the patients are assessable for toxicity; the G3-4 maximum observed toxicities were: neutropenia 40% (febrile neutropenia 2%), anemia 4%, diarrhea 11%, nausea 4%, stomatitis 2%, deep venous thrombosis 4% and hypertension 9%; G1 bleeding occurred in 15 pts (26%). No toxic deaths have occurred. Up today 51 pts have been evaluated for response and we observed 6 CR, 32 PR (ORR = 75%) and 13 SD (disease control rate = 100%). So far 8 pts (16%) have undergone to secondary surgery on liver mts and 7 R0 resections have been performed. After a median follow up of 7.7 months, the 10 months actuarial PFS is 73%.

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. Data on activity are very promising. The study is still ongoing to complete the follow-up and to better determine the efficacy of the combination. A phase III study comparing FOLFIRI+BV vs FOLFOXIRI+BV has been planned by the GONO group.

BACKGROUND

The best outcome of mCRC is achieved in pts receiving 5FU, irinotecan, and oxaliplatin in the course of their disease, and the resection-rate of metastases increases with the increase of the response-rate to first-line treatment. A way to expose 100% of pts to all the 3 cytoxic agents and to improve the response-rate is to incorporate them into the first-line therapy. (Grothey JCO 2004, Folprecht Ann Oncol 2005)

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 JCO 2007)

Bevacizumab associated with IFL is feasible and significantly improves response rate, progression free and overall survival compared to IFL alone in the first-line treatment of MCRC pts. (Hurwitz NEJM 2004)

Bevacizumab associated with oxaliplatin-based chemotherapy (FOLFOX or XELOX) is feasible and significantly improves efficacy compared to chemotherapy alone in first- and second-line treatment of MCRC pts. (Giantonio JCO 2007, Saltz JCO 2008)

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

OBJECTIVES

PRIMARY

Percentage of patients free of progression at 10 months

SECONDARY

Response rate

R0 surgery of mets

Progression free survival

Overall survival

Safety profile

Evaluation of potential surrogate markers predictive of bevacizumab activity

MAIN SELECTION CRITERIA

INCLUSION 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 CT allowed if more than 12 months have elapsed between the end of adjuvant therapy and first relapse

Adequate liver, renal and bone marrow functions

Urine dipstick for proteinuria < 2+

EXCLUSION CRITERIA Prior palliative chemotherapy or treatment with bevacizumab

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

STATISTICS

In phase II and III studies both the FOLFOXIRI regimen and the

combination of bevacizumab with IFL regimens produced a median

progression free survival of about 10 months (50% of patients free of

progression at 10 months).

The combination of FOLFOXIRI with bevacizumab will be considered

promising in terms of activity if the percent of patients free of progression

at 10 months will increase from 50% to 70%.

According to the single-stage design described by Fleming, and

selecting the design parameters p0 (percent of patients free of progression

at 10 months in null hypothesis) = 0.50, and p1 (percent of patients free of

progression at 10 months in alternative hypothesis) = 0.70, and considering

also an α and β errors of 0.05 and 0.10, the study required a total of 53

evaluable patients.

Treatment will be judged promising if at least 33 out of 53 patients free of

progression at 10 months will be observed.

STUDY DESIGN

FOLFOXIRI plus Bevacizumab was planned for a maximum of 12 cycles, or

until progressive disease, or unacceptable toxicities, or patients’ refusal.

Maintainance Bevacizumab* was recommended after the first 12 cycles

until progressive disease, or unacceptable toxicities or patients’ refusal.

Surgical radical resection of residual metastases in responsive patients

was highly recommended and its feasibility was evaluated every 2 months.

After resection it was recommended to restart FOLFOXIRI plus

Bevacizumab (or a different treatment based on previous toxicities) to

receive a total of 12 cycles of CT including those administered before

surgery. Bevacizumab* was continued for a maximum of 12 months after

resection or until tumor progression, unacceptable toxicity, or patient

refusal.

* On March 2008 the protocol was emended and Bevacizumab + 5FU/LV was recommended as maintainance treatment.

FOLFOXIRI + BEVACIZUMAB SCHEDULE

So far, 640 total cycles of treatment have been administered: 506 cycles with FOLFOXIRI plus Bevacizumab and 134 cycles of maintanance treatment with Bevacizumab (in 1 patient with Bevacizumab plus 5FU/LV).

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’ CHARACTERISTICS

N %

Patients 57 -

Age, median (range) 61 (34-75) -

Sex (M/F) 34/23 60/40

ECOG PS 0/1/2 39/15/3 69/26/5

Primary site (colon/rectum) 41/16 72/28

Surgery for primary tumor (y/n) 44/13 77/23

Previous adjuvant CT (y/n) 5/52 9/91

Sites of disease (single/multiple)

32/25 56/44

Liver only mts 30 53

FOLFOXIRI + BEVACIZUMAB TOXICITY (maximum toxicity per patient; N=57)

Toxicity G1 (%) G2 (%) G3 (%) G4 (%)

Nausea 39 30 4 0

Vomiting 25 28 0 0

Diarrhea 33 21 11 0

Stomatitis 32 21 2 0

Neutropenia 19 19 23 17

Febrile Neutropenia 0 0 0 2

Thrombocytopenia 37 0 0 0

Anemia 49 35 4 0

Neurotoxicity 35 28 0 0

Hypertension 14 5 9 0

Deep venous thrombosis 2 0 4 0

Bleeding 26 2 0 0

Cardiac ischemia 0 0 4 0

No toxic deaths have so far occurred.

Toxicity G1 (%) G2 (%) G3 (%) G4 (%)

Nausea 13 4 0 0

Vomiting 4 4 0 0

Diarrhea 0 0 0 0

Stomatitis 13 4 0 0

Neutropenia 0 0 4 0

Febrile Neutropenia 0 0 0 0

Thrombocytopenia 17 0 0 0

Anemia 22 9 4 0

Neurotoxicity 9 43 0 0

Hypertension 0 0 13 0

Deep venous thrombosis 0 0 0 0

Bleeding 13 0 0 0

Cardiac ischemia 0 0 0 0

MAINTAINANCE BEVACIZUMAB ± 5FU/LV TOXICITY (maximum toxicity per patient; N=23)

No toxic deaths have so far occurred.

RESPONSE RATE (RECIST CRITERIA)

Total evaluable patients* N=51

Complete Response (CR) 6 12%

Partial Response (PR) 32 63%

Overall Response Rate 38 75%

Stable Disease (SD) 13 25%

Progressive Disease 0 0

Disease Control Rate

(CR + PR + SD)51 100%

*6 patients too early

R0-SURGERY

So far 8 pts (16%) with liver only metastases have undergone to secondary surgery on liver mts; 7 R0 and 1 R1 resections have been performed (data still immature)

2 patients have achieved a confirmed pCR

No deaths and no relevant morbidities have been observed after surgery

6 patients have received postoperative treatment: 3 with FOLFOXIRI plus Bevacizumab 1 with FOLFOXIRI 1 with FOLFIRI plus Bevacizumab 1 with Bevacizumab alone

PROGRESSION-FREE and OVERALL SURVIVAL

Data on PFS and OS are promising, but still immature

Median Follow-up is 7.7 months

14 (25%) pts have so far progressed

At 10 months actuarial PFS is 73%

1 (2%) patient have died

CONCLUSIONS The addiction of BV to the GONO-FOLFOXIRI regimen is feasible with manageable toxicities

The characteristic toxicities of BV and FOLFOXIRI occur with the expected incidence and there were not unexpected adverse events

Treatment activity is very promising (RR=75%, Disease Control Rate= 100%, actuarial PFS at 10 months= 73%)

Data on surgery of metastases, PFS and OS are still immature, but promising

The accrual has been completed; the follow-up of enrolled patients is ongoing to better evaluate the efficacy

A phase III study comparing FOLFIRI+BV vs FOLFOXIRI+BV has been planned by the GONO group

ACKNOWLEDGEMENTS

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

Prato Ciarlo A, Cavaciocchi D, Di Leo A.

Roma Ferraldeschi R, Puglisi M, Cortesi E.

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.