Trial Information

Pre- and Postoperative Chemotherapy Including Bevacizumab in Potentially Curable Metastatic Colorectal Cancer (mCRC). A Multicenter, Single Arm Phase I/II Academic Trial

Major attempt is being given to the potential of curing patients with metastatic colorectal
cancer due to the recognition of dramatic change in survival figures achieved in palliative
chemotherapy combination treatment protocols. Achieving resectablity rates in previously
unresectable patients has been defined as study endpoint among other well known primary and
secondary objectives. Curing metastatic colorectal cancer is most likely in resectable
patients and therefore the logical next step after completion of chemotherapy combination
studies (e.g. EORTC 40983) is the addition of targeted agents. Bevacizumab has the most
valid data of improving outcome figures and was therefore chosen as additional agent. Safety
of the combination with Xelox was demonstrated in our pilot trial (Gruenberger JCO 2006,
ASCO 2006, WCGC 2006, ESMO 2006), consequently response rate and resection rate will be the
primary endpoints in this trial.

STUDY OBJECTIVES

Primary Objective The primary objective of this study is the Resectability (R0) rate after
neoadjuvant Bevacizumab in potentially resectable mCRC.

Secondary Objectives The secondary objectives of this study include

- Feasibility with regards to GI bleeding and wound healing complications after surgery
of liver metastases

- General safety

- Overall Response Rate (ORR)

- Recurrence Free Survival (RFS)

- Overall Survival (OS)

STUDY DURATION Recruitment is planned for 12 months. Patients will be treated for 6 cycles
XELOX and 5 cycles Bevacizumab. Surgery will be performed 2 weeks after the last
Capecitabine administration, allowing a time window of 5 weeks between the last Bevacizumab
administration and surgery.

Therapy with 6 cycles of XELOX and Bevacizumab will be restarted 4-5 weeks after surgery.

With a Follow up period of 2 years after the last enrolled patient, in order to assess RFS
and OS, the trial will last for approx. 3 years.

NUMBER OF CENTRES Four centres with a high level of experience in the surgery of liver
metastases are planned to participate in this study.

SELECTION CRITERIA

Total Number of Patients and Target Population The planned total sample size for this study
is 40 patients. Patients with potentially resectable metastatic colorectal cancer previously
untreated for metastatic disease will be enrolled in this trial.

STUDY DESIGN

Design This is a single arm, multicenter Phase I/II trial to evaluate the Resectability (R0)
rate after neoadjuvant Bevacizumab in combination with a biweekly regime of capecitabine
plus oxaliplatin (XELOX) in potentially resectable mCRC.

The pre-operative treatment phase consists of 6 cycles XELOX and 5 cycles Bevacizumab. The
cycle duration is 2 weeks.

Surgery will be performed 2 weeks after the last administration of Capecitabine, allowing a
time window of 5 weeks between the last dose of Bevacizumab and surgery.

The post-operative treatment phase consists of 6 cycles XELOX + Bevacizumab and will be
re-started 4-5 weeks after surgery.

Patients will be further followed for tumour progression and survival for a further 2 years
after the last patient has been enrolled in this trial (end of the study follow up).

Schedule of Assessment and Study Procedures Study assessments and procedures will be
performed as shown in Table 1 and 2. Screening and Baseline Written informed consent must be
obtained prior to the patient undergoing any study-specific procedures.

1. Tumor assessments: abdominal and pelvic CT / MRI and chest CT / MRI may be obtained up
to 4 weeks prior to enrollment.

2. Assessments to be made up to 14 days before enrollment include: demographic data,
medical history, cancer/treatment history, concomitant disease/treatment, physical
examination (including basic neurologic exam by investigator), electrocardiogram (ECG)
and CEA, CA 19-9 determination.

3. Assessments to be made within 7 days before enrollment: height, weight, vital signs
(body temperature, blood pressure, and pulse/heart rate), ECOG Performance Status,
hematology, blood chemistry (including creatinine clearance calculation), INR & aPTT,
serum pregnancy test (for all women less than 2 years amenorrheic), dipstick urinalysis
for proteinuria, and 24-hour urine collection for determination of total protein (if
necessary).

4. Urine pregnancy test is required prior to first administration of study treatment if
more than 7 days have elapsed from baseline serum pregnancy test.

If a Central Venous Access Device (CVAD) is required, at least a 2-day interval between
placement of a central line and first bevacizumab administration is recommended.

Treatment Phase (pre- and post-operative) Standard Clinical Assessments

- Physical examination (including basic neurologic exam by investigator)

- ECOG performance status (see Appendix 4)

- Vital signs [weight, body temperature, blood pressure, pulse/ heart rate]

- On each (scheduled) visit, patients will be assessed for adverse events (grading by the
common terminology criteria for adverse events (CTCAE version 3.0).

Laboratory Assessments

The following laboratory tests are to be done:

- White blood cell count with differentials (lymphocytes, neutrophils), red blood cell
count, hemoglobin, hematocrit and platelet count

- Bilirubin (total and direct), ASAT, ALAT, alkaline phosphatase, albumin, LDH

- Serum creatinine

- Glucose

- Electrolytes (sodium, potassium)

- Calcium

- INR (for patients receiving oral anticoagulant treatment)

- CEA, CA 19-9

- Urinalysis: dip stick test for protein is to be performed before each administration of
bevacizumab.

- Serum pregnancy tests (if clinically indicated)

Surgery and Control Visits after Surgery

The first control visit should be performed 10 days after surgery and should include the
following assessments:

- ECOG performance status

- Vital signs [weight, body temperature, blood pressure, pulse/ heart rate]

- Haematology, Blood chemistry and Coagulation

- Adverse events (grading by the common terminology criteria for adverse events (CTCAE
version 3.0) with special regard to wound healing

The second control visit will be performed 21 days after surgery and should include the same
assessments as on the first control visit with the addition of:

- Physical examination

- Electrocardiogram (ECG)

- Tumour Assessment

Final Visit End of treatment safety visit to be performed 28 days after the last drug
administration.

Follow up Phase and Termination of Study Progression Free Survival Status and Survival
status should be assessed every 3 months for a maximum of 2 years.

STUDY MEDICATION

Dose, Schedule and Administration Bevacizumab Bevacizumab will be given at 5 mg/kg on d1
every two weeks, for 5 consecutive cycles. The 6th cycle will be XELOX without Bevacizumab,
allowing for a time window between last administration of Bevacizumab and surgery of 5
weeks.

The time window between surgery and re-start of treatment will be at least 4 weeks and wound
healing must be completed. Bevacizumab will then be given at 5 mg/kg on d1 every two weeks,
for 6 consecutive cycles in combination with XELOX.

Bevacizumab doses will be calculated for each patient in milligrams per kilogram. The
patient's actual weight from the screening visit will be the reference weight throughout the
study (i.e., patients will receive the same dose at each treatment). Doses of Bevacizumab
will be recalculated for patients who experience more than 10% change in body weight from
baseline during the treatment period.

All patients will receive an infusion of study drug in a total volume of 100 mL of 0.9%
Sodium Chloride Injection, USP. Bevacizumab infusions should not be administered or mixed
with dextrose or glucose solutions.

The initial study drug dose will be delivered over 90 minutes as a continuous IV infusion.
If the first infusion is tolerated without infusion associated adverse events the second
infusion may be delivered over 60 minutes. If the 60 minute infusion is tolerated, all
subsequent infusions may be delivered over 30 minutes. If a patient experiences infusion
associated adverse events with the 60 minute infusion, all subsequent doses will be given
over 90 minutes. If a patient experiences infusion associated adverse events with the 30
minute infusion, all subsequent doses will be given over 60 minutes.

Should extravasation of the study drug infusion occur, the following steps are to be taken:

1. Discontinue the IV.

2. If a significant volume of the study drug infusion remains, restart the IV at a more
proximal site in the same limb

3. Treat the infiltration according to institutional guidelines for infiltration of a
noncaustic agent.

In the pre-surgery phase, Bevacizumab will be obtained locally by prescription. After
surgery, Bevacizumab will be supplied as glass vials with 4-mL fill, containing 100 mg (25
mg/mL) or with 16-mL fill, containing 400 mg (25 mg/mL). Vials contain no preservative and
are for single use only.

Oxaliplatin Liquid Oxaliplatin will be given at 85 mg/m2 on d1 every two weeks, for 6
consecutive cycles, before and after surgery.

Liquid Oxaliplatin dose will be calculated using the body surface area (BSA) of the patient
(see Appendix 2). The dose of oxaliplatin administered should be as close as possible to the
calculated dose.

Liquid Oxaliplatin administration does not require hyperhydration. In the event of
extravasation, administration must be discontinued immediately.

For nausea and vomiting, 5-HT3 antagonists with or without dexamethasone are strongly
recommended for oxaliplatin-based chemotherapy.

Liquid Oxaliplatin must be infused either by peripheral vein or central venous line over 2
hours. The infusion line must be adequately flushed with 5% dextrose solution (D5W) between
oxaliplatin infusion and the administration of any other drug.

Liquid Oxaliplatin (Eloxatin®) will be obtained locally by prescription.

Capecitabine The dose of Capecitabine is 1.500 mg/m2 twice daily from the evening of d1
until the morning of d8, followed by 1 week rest period. One treatment cycle consists of 2
weeks. Capecitabine will be given for 6 consecutive cycles, before and after surgery.

The appropriate daily dose of capecitabine is identified by determination of the Body
Surface Area (see Appendix 2 and 3).

Capecitabine is to be administered orally within 30 minutes after the end of a meal
(breakfast, dinner). Tablets should be swallowed with approximately 200 mL water (not fruit
juices). The first dose of each cycle will be administered as the evening dose on day 1 and
the last dose of each cycle is scheduled the morning of day 8, followed by a 7 day rest
period.

Capecitabine (Xeloda®) will be obtained locally by prescription.

Study Treatment Duration In the pre-operative treatment phase 6 cycles of XELOX and 5 cycles
of Bevacizumab will be administered, resulting in a total treatment duration of 12 weeks.

Surgery will be performed 2 weeks after the last administration of Capecitabine.

Post-operative treatment consists of 6 cycles XELOX + Bevacizumab and will re-start 4-5
weeks after surgery.