The Combination of Bevacizumab (Bev) with capecitabine/irinotecan (CapIri/Bev) or capecitabine/oxaliplatin

(CapOx/Bev) is highly active in advanced colorectal cancer (ACRC): A randomized phase II study of the AIO Colorectal

Study Group (AIO trial 0604)

A. Reinacher-Schick1, S. Kubicka2, W. Freier3, D. Arnold4, G. Dietrich5, M. Geißler6, S. Hegewisch-Becker7, U. Graeven8, H.-J. Schmoll4 and W. Schmiegel1,

Ruhr University Bochum1, University Hannover2, Center of Oncology Hildesheim3, Martin-Luther-University Halle-Wittenberg4, Hospital Bietigheim, Bietigheim-Bissingen5, Community Hospital Esslingen6, Center of Oncology Eppendorf, Hamburg7, Maria Hilf Hospital Mönchengladbach8,

Germany

• Addition of Bevacizumab to 5FU/FA/irinotecan1 and 5FU/FA/oxaliplatin2,3 improves progression free survival (PFS) in advanced CRC (aCRC)

• Efficacy of Capecitabine/Oxaliplatin (CapOx) is similar to 5-FU/FA/Oxaliplatin

• Data on Capecitabine/Irinotecan (CapIri) combinations remains controversial, due to toxicity 4-7

1 Hurwitz, N Engl J Med 2004; 2 Giantonio, JCO 2007; 3 Saltz, JCO 2008; 4 Fuchs, JCO 2007; 5 Köhne, Ann Oncol 2008; 6 Grothey, ASCO 2003; 7 Koopman, Lancet 2007

Background

Aim

To investigate whether bevacizumab in combination with

CapOx or CapIri is effective for patients with aCRC

Study Design

Open-label, multicenter, randomized phase II study

Primary endpoint:Rate of pts. without disease progression at 6 months: Exclude insufficient activity (defined as rate < 60%)

Secondary endpoints:Overall survival, toxicity, resectability of liver/lung mets.

Main eligibility criteria

- written informed consent

- histologically proven aCRC, measurable lesion (RECIST)

- Age > 18 years

- ECOG performance status < 2

- Adequate haematological, renal and hepatic function

- no previous systemic immunotherapy or chemotherapy

(except (neo)adjuvant therapy for non-metastatic disease > 6 months)

- history of thrombosis or severe bleeding < 6 months, bleeding diathesis, therapeutic anticoagulation

- proteinuria < +1 by dipstick urin analysis

Treatment protocolArm A: d 1

d 15

Oxaliplatin130mg/m2, 120min i.v.Bevacizumab 7,5 mg/kg i.v. Capecitabine 1000mg/m2 p.o., 2x daily

Arm B: (*)Irinotecan200mg/m2, 30min i.v.Bevacizumab 7,5 mg/kg i.v. Capecitabine800mg/m2 p.o., 2x daily

q 3wks

note dose reduction of CapIri compared to previous trials for safety reasons

Patient accrualRekrutierungsbersicht

0

50

100

150

200

250

300

Jul05

Aug05

Sep05

Oct05

Nov05

Dec05

Jan06

Feb06

Mar06

Apr06

May06

Jun06

Jul06

Aug06

Sep06

Oct06

Soll

Ist

observedexpected

Baseline characteristics (n=247) No. Patients

Arm A127

Arm B120

Median age (range), years 64 (27-83) 64.5 (30-82) Distribution of age, % < 40 years 4 2 40-49 years 8 7 50-59 years 23 23 60-69 years 35 42 70-79 years 29 22 > 80 years 2 2 Male, female % 66 / 34 67 / 33 ECOG Performance status, %

0 52 52 1 45 46 2 3 2

Prior adjuvant therapy, % No 77 79 Yes 23 21

Treatment characteristics (n=247)

Number of pats.

Arm A127

Arm B120

Total247

Number of cycles (evaluable pats.)

1158 1269 2427

Mean no. of cycles (+/- SD)

9.1 (+/- 6.7) 10.6 (+/-7.1) 9.9 (+/-6.9)

Range 1-37 1-38 1-38

Median 8 9 9

Reasons for end of treatment, EOT (n=222)

Reason for EOT

n

Arm A

116

Arm B

108

Total

222

Disease Progression

46 (40%) 35 (32%) 81 (36%)

Progression free 70 (60%) 73 (68%) 143 (64%)

- toxicity 27 (39%) 12 (16%) 39 (27%)

- SAE 5 (7%) 8 (11%) 13 (9%)

- death, not tumor related

4 (6%) - 4 (3%)

- protocol violation 2 (3%) 5 (7%) 7 (5%)

- consent withdrawn 11 (16%) 14 (19%) 25 (17%)

- lost to follow-up 1 (1%) 2 (3%) 3 (2%)

- Resection/Ablation 4 (6%) 6 (8%) 10 (7%)

- Other 16 (23%) 26 (36%) 42 (29%)*end of treatment information available for n=222 pts.

CTC V. 3.0 Grade 3 and 4 Toxicities (n=247)

Related toxicities

Arm A (127)3°/4° [%]

Arm B (120)3°/4° [%]

Diarrhoea 21/0 16/0

Sensory neuropathy 24/1 0

Hand-Foot-Syndrome 11/0 8/0

Neutropenia 2/0 8/2

Thrombocytopenia 6/0 0

Fatigue 2/1 3/0

Ileus 2/1 2/0

Nausea 3/0 3/0

Vomiting 4/0 5/0

AEs of special interest (n=247)

AEs of special interest (Bev)

Arm A (127)3°/4° [%]

Arm B (120)3°/4° [%]

Thrombosis/Embolism - venous access thrombosis - other (incl. pulmonary emb.)

3/21/02/2

4/11/03/1

Hypertension 4/0 3/0

Cardiac ischemia/infarction 0 0/1

Hemorrhage/bleeding (GI) 1/0 0

Best overall response* (n=247)

Arm A

% of patients(n =127)

Arm B% of patients

(n =120)

CR 5 6 PR 48 49 SD 29 28 PD 5 6 NE/NA** 13 11

*ITT, RECIST criteria, investigator‘s assessment; **not evaluated/not available

PFS rate after 6 months: Primary endpoint

Arm A% of patients

(n =127)

Arm B% of patients

(n =120)

PFS rate/6 mo.

76 84

months

rate

with

out p

rogr

essi

on

0 6 12 18 24 30 36

0.0

0.2

0.4

0.6

0.8

1.0

Progression-free Survival by Treatment

Logrank test: p = 0.27

A : n = 127, 98 events, median = 10.4 monthsB : n = 120, 91 events, median = 12.1 months

Fig. 4.2_______

Progression free survival (PFS) - ITT analysis

months

rate

with

ou

t pro

gre

ssio

n

0 6 12 18 24 30 36

months

0.0

0.2

0.4

0.6

0.8

1.0

surv

ival

rat

e

Overall Survival by Treatment

Fig. 4.5_______

Logrank test: p = 0.55

A : n = 127, 46 events, median = 26.7 monthsB : n = 120, 40 events, median = NA

months

Su

rviv

al r

ate

Overall survival (OS) - ITT analysis

Conclusion• Both regimens, CapOx/Bev and CapIri/Bev,

are highly active in aCRC.

• The dose reduction of CapIri/Bev may lead to a favourable toxicity profile compared to previous capecitabine/irinotecan trials seemingly without compromising efficacy

• The CapIri/Bev arm - compared to the CapOx/Bev arm - seems to be associated with higher cycle numbers and a tendency towards longer PFS

Acknowledgements

We would like to thank

- the patients and their families- the co-investigators- the study nurses and data monitors- Roche Pharma AG and Sanofi-Aventis for financial support