Randomized phase II trial evaluating the efficacy of FOLFOX alone, FOLFOX plus bevacizumab and FOLFOX plus panitumumab as perioperative treatment in patients with resectable liver metastases form wild type KRAS colorectal cancer. EORTC 40091.

Recruitment & Eligibility

Status: Completed

Sex: Not specified

Target Recruitment: 35

Inclusion Criteria

- Histologically proven CRC with 1 to 8 metachronous or synchronous
liver metastases considered to be completely resectable. (Defined in
section 5.5).
- Primary tumor (or liver metastasis) of CRC must be KRAS status *wild
type*.
- Patients must have undergone complete resection (R0) of the primary
tumor at least 4 weeks before randomization. Or for patients with
synchronous metastases the primary tumor can be resected (R0) at the
same time as the liver metastases if: the patient has a non-obstructive
primary tumor and is able to receive preoperative chemotherapy (3-4
months) before surgery.
- Measurable hepatic disease by Response Evaluation Criteria in Solid
Tumors (RECIST version 1.1).
- No evidence of extra-hepatic metastasis (of CRC).
- Patients must be 18 years old or older.
- A World Health Organization (WHO) performance status of 0 or 1.
- No previous chemotherapy for metastatic disease or surgical treatment
(e.g. surgical resection or radiofrequency ablation) for liver metastasis.
Radiotherapy alone is allowed if given pre or post protocol treatment.
- Previous adjuvant chemotherapy for primary CRC is allowed if
completed at least 12 months before inclusion in this study.
- No major surgical procedure, open biopsy, or significant traumatic
injury within 4 weeks prior to randomization.
- All the following tests should be done within 4 weeks prior to
randomization:
- Absolute neutrophil count >= 1.5 x 109/L, platelets >= 100 x 109/L,
hemoglobin >= 9 g/dL and white blood cell count (WBC) >= 3 x
109/L.
- Serum creatinine <= 1.5 times the upper limit of normal (ULN) (to
exclude severe renal impairment); no significant proteinuria (urine
protein < 1g/24 hours urine collection) OR urine protein/creatinine
ratio < 1.0 OR 1+ proteinuria on urine dipstick.
- Absence of major hepatic insufficiency (bilirubin <= 1.5 x ULN and
aspartate aminotransferase (ASAT) and alanine aminotransferase
(ALAT) <= 5 x ULN).
- Magnesium >= lower limit of normal (LLN)
- Patients with a buffer range from the normal values of +/- 5% for
hematology and +/- 10% for biochemistry are acceptable. This will
not apply for Renal Function, including Creatinine.
- No previous exposure to Epidermal Growth Factor Receptor (EGFR) or
Vascular Endothelial Growth Factor Receptor (VEGF/VEGFR)
targeting therapy within the last 12 months.
- No regular use of aspirin or other non-steroidal anti-inflammatory drugs
(NSAIDs).
- No bleeding diathesis (e.g. hemoptysis of >= 1/2 teaspoon or 2.5mL),
coagulopathy, or need for administration of full-dose anti-coagulant(s).
- Absence of peripheral neuropathy > grade 1 (Common Terminology
Criteria for Adverse Events, v4.0) serious wound complications, ulcers,
or bone fractures.
- No clinically significant cardiovascular disease, including: uncontrolled
hypertension, New York Heart Association (NYHA) class II-IV heart
failure, myocardial infarction or unstable angina pectoris,
cerebrovascular accident or transient ischemic attack within the past 12
months, peripheral vascular disease >= grade 2, serious cardiac
arrhythmia requiring medication and other clinically significant
cardiovascular disease.
-Absence of symptomatic diverticulitis or active or uncontrolled
gastroduodenal ulceration.
- No history or evidenc

Exclusion Criteria

not resectable liver metastases
extra hepatic disease

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>to detect an increase in progression free survival (PFS*, see chapter 7.3.6)<br /><br>rate at 1 year in each experimental arm (mFOLFOX6 + bevacizumab or panitumumab)<br /><br>compared to mFOLFOX6 alone arm as perioperative treatment for resectable liver<br /><br>metastasis from wild type Kirsten rat sarcoma viral oncogene homolog (KRAS)<br /><br>colorectal cancer (CRC). </p><br>

Secondary Outcome Measures

Name	Time	Method
<p>to assess the pathological response rate and detect an increase in major<br /><br>pathological response rate between mFOLFOX6 alone arm and each experimental<br /><br>arm. Others objectives are correlation between pathological response and<br /><br>disease free survival (DFS), resection rate, response rate, PFS*, overall<br /><br>survival and safety. </p><br>