Brief Summary

Colorectal cancer patients with initially unresectable liver-only metastases may be cured after downsizing of metastases by neoadjuvant systemic therapy. However, the optimal neoadjuvant induction regimen has not been defined, and no consensus exist on criteria for resectability. In this study colorectal cancer patients with initially unresectable liver-only metastases, as prospectively confirmed by an expert panel according to predefined criteria, will be tested for RAS and BRAF tumor mutation status and selected by location of primary tumor. Patients with RAS or BRAF mutant and/or right sided tumors will be randomised between doublet chemotherapy (FOLFOX or FOLFIRI) plus bevacizumab (schedule 1), and triple chemotherapy (FOLFOXIRI) plus bevacizumab (schedule 2). Patients with RAS AND BRAF wildtype AND left-sided primary tumors will be randomized between doublet chemotherapy (FOLFOX or FOLFIRI) plus either bevacizumab (schedule 1) or panitumumab (schedule 3). Patient imaging will be reviewed for resectability by a central panel, consisting of at least one radiologist and three surgeons every assessment. Central panel review will be performed prior to randomization as well as during treatment, as described in the protocol.

Trial Health

On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment

530

participants targeted

Target at P50-P75 for phase_3 colorectal-cancer

Timeline

Completed

Started Jul 2014

Longer than P75 for phase_3 colorectal-cancer

Geographic Reach

2 countries

56 active sites

Status

completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

10.5 years study duration

First Submitted

Initial submission to the registry

June 5, 2014

Completed

7 days until next milestone

First Posted

Study publicly available on registry

June 12, 2014

Completed

19 days until next milestone

Study Start

First participant enrolled

July 1, 2014

Completed

8 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

July 1, 2022

Completed

2.5 years until next milestone

Study Completion

Last participant's last visit for all outcomes

January 1, 2025

Completed

Last Updated

February 6, 2025

Status Verified

February 1, 2025

Enrollment Period

8 years

First QC Date

June 5, 2014

Last Update Submit

February 4, 2025

Conditions

Colorectal Cancer Liver Metastases

Keywords

Colorectal cancerChemotherapyAnti-EGFRLiver metastasesR0 R1 liver resectionResectability of liverLiver expert panel

Outcome Measures

Primary Outcomes (1)

Progression-free survival (PFS)
Time from registration until progression or death whichever comes first
2 years after last patient in study

Secondary Outcomes (7)

R0/1 secondary resection rate
2 years after last patient in study
Median overall survival
8 years after last patient in study
Response rate
2 years after last patient in study
Toxicity (AE)
2 years after last patient in study
Pathological complete response rate (pCR)
2 years after last patient in study
+2 more secondary outcomes

Study Arms (4)

Arm B: FOLFOXIRI & bevacizumab (inclusion completed)

EXPERIMENTAL

Patients with RAS or BRAF mutated and/or right-sided tumors will receive 5FU, irinotecan, oxaliplatin (FOLFOXIRI) and bevacizumab. Intervention: FOLFOXIRI with bevacizumab

Drug: FOLFOXIRI with bevacizumab

Arm A: FOLFOX/FOLFIRI & bevacizumab (inclusion completed)

ACTIVE COMPARATOR

Patients with RAS or BRAF mutated and/or right-sided tumors will receive doublet fluoropyrimidine-containing chemotherapy (FOLFOX or FOLFIRI), plus bevacizumab. Intervention: FOLFOX/FOLFIRI with bevacizumab

Drug: FOLFOX/ FOLFIRI with bevacizumab

Arm D: FOLFOX/FOLFIRI & panitumumab

EXPERIMENTAL

Patients with RAS and BRAF wildtype and left-sided tumors will receive doublet fluoropyrimidine-containing chemotherapy (FOLFOX or FOLFIRI), plus panitumumab. Intervention: FOLFOX/FOLFIRI with panitumumab

Drug: FOLFOX/ FOLFIRI with panitumumab

Arm C: FOLFOX/ FOLFIRI & bevacizumab

ACTIVE COMPARATOR

Patients with RAS and BRAF wildtype and left-sided tumors will receive doublet fluoropyrimidine-containing chemotherapy (FOLFOX or FOLFIRI), plus bevacizumab. Intervention: FOLFOX/FOLFIRI with bevacizumab

Drug: FOLFOX/ FOLFIRI with bevacizumab

Interventions

FOLFOX/ FOLFIRI with bevacizumabDRUG

FOLFIRI + bevacizumab Bevacizumab 5 mg/kg in 15-30 minutes i.v., followed by irinotecan 180 mg/m2 i.v. in 60 minutes together with leucovorin 400 mg/m2 i.v. in 120 minutes, followed by bolus 5-fluorouracil 400 mg/m2 within 4 minutes, all on day 1, followed by continuous infusion of 5-fluorouracil 2400 mg/m2 in 46 hours, every 2 weeks FOLFOX6 + bevacizumab Bevacizumab 5 mg/kg in 15-30 minutes i.v., followed by oxaliplatin 85 mg/m2 i.v. together with leucovorin 400 mg/m2 i.v. in 120 minutes, followed by bolus 5FU 400 mg/m2 within 4 minutes, all on day 1, followed by continuous infusion of 5-fluorouracil 2400 mg/m2 in 46 hours, every 2 weeks

Also known as: - bevacizumab, - irinotecan, - leucovorin, - 5-fluorouracil, - oxaliplatin

Arm A: FOLFOX/FOLFIRI & bevacizumab (inclusion completed)Arm C: FOLFOX/ FOLFIRI & bevacizumab

FOLFOXIRI with bevacizumabDRUG

FOLFOXIRI + bevacizumab Bevacizumab 5 mg/kg in 15-30 minutes i.v., followed by irinotecan 165 mg/m2 i.v. in 60 minutes, followed by oxaliplatin 85 mg/m2 i.v. together with leucovorin 400 mg/m2 i.v. in 120 minutes, followed by continuous infusion of 5-fluorouracil 3200 mg/m2 in 46 hours, every 2 weeks

Also known as: - bevacizumab, - irinotecan, - oxaliplatin, - leucovorin, - 5-fluorouracil

Arm B: FOLFOXIRI & bevacizumab (inclusion completed)

FOLFOX/ FOLFIRI with panitumumabDRUG

FOLFIRI + panitumumab Panitumumab 6 mg/kg i.v. (1st dose in 60 minutes, if well tolerated subsequent doses in 30 minutes), followed by irinotecan 180 mg/m2 i.v. in 60 minutes together with leucovorin 400 mg/m2 i.v. in 120 minutes, followed by bolus 5-fluorouracil 400 mg/m2 within 4 minutes, all on day 1, followed by continuous infusion of 5-fluorouracil 2400 mg/m2 in 46 hours, every 2 weeks FOLFOX6 + panitumumab Panitumumab 6 mg/kg i.v. (1st dose in 60 minutes, if well tolerated subsequent doses in 30 minutes), followed by oxaliplatin 85 mg/m2 i.v. together with leucovorin 400 mg/m2 i.v. in 120 minutes, and bolus 5FU 400 mg/m2 within 4 minutes, all on day 1, followed by continuous infusion of 5-fluorouracil 2400 mg/m2 in 46 hours, every 2 weeks

Also known as: - panitumumab, - irinotecan, - leucovorin, - 5-fluorouracil, - oxaliplatin

Arm D: FOLFOX/FOLFIRI & panitumumab

Eligibility Criteria

Age18 Years+

Sexall

Healthy VolunteersNo

Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

Histological proof of colorectal cancer
Initially unresectable metastases confined to the liver according to CT scan, obtained ≤3 weeks prior to registration. Unresectability should be confirmed by the liver expertpanel. Patients with small (≤ 1 cm) extrahepatic lesions that are not clearly suspicious of metastases are eligible
Known mutation status of RAS and BRAF
WHO performance status 0-1 (Karnofsky performance status ≥ 70)
Age ≥ 18 years
No contraindications for liver surgery
In case of primary tumor in situ: tumor should be resectable
In case of resected primary tumor: adequate recovery from surgery
Adequate organ functions, as determined by normal bone marrow function (Hb ≥ 6.0 mmol/L, absolute neutrophil count ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L), renal function (serum creatinine ≤ 1.5x ULN and creatinine clearance, Cockroft formula, ≥ 30 ml/min), liver function (serum bilirubin ≤ 2 x ULN, serum transaminases ≤ 5x ULN)
Life expectancy \> 12 weeks
Expected adequacy of follow-up
Written informed consent

You may not qualify if:

Extrahepatic metastases, with the exception of small (≤ 1 cm) extrahepatic lesions that are not clearly suspicious of metastases
Unresectable primary tumor
Serious comorbidity or any other condition preventing the safe administration of study treatment (including both systemic treatment and surgery)
Major cardiovascular events (myocardial infarction, severe/unstable angina, congestive heart failure, CVA) within 12 months before randomisation
Uncontrolled hypertension, or unsatisfactory blood pressure control with ≥3 antihypertensive drugs
Previous systemic treatment for metastatic disease; previous adjuvant treatment is allowed if completed ≥ 6 months prior to randomisation
Previous surgery for metastatic disease
Previous intolerance of study drugs in the adjuvant setting
Pregnant or lactating women
Second primary malignancy within the past 5 years with the exception of adequately treated in situ carcinoma of any organ or basal cell carcinoma of the skin, or second primary colorectal cancer.
Any concomitant experimental treatment.

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Dutch Colorectal Cancer Grouplead

Study Sites (56)

Universitair ziekenhuis Antwerpen

Antwerp, Belgium

Location

Flevoziekenhuis

Almere Stad, Flevoland, Netherlands

Location

Gelre Ziekenhuis

Apeldoorn, Gelderland, Netherlands

Location

Rijnstate ziekenhuis

Arnhem, Gelderland, Netherlands

Location

Sint Jansdal Ziekenhuis

Harderwijk, Gelderland, Netherlands

Location

Radboud UMC

Nijmegen, Gelderland, Netherlands

Location

Streekziekenhuis Koningin Beatrix

Winterswijk, Gelderland, Netherlands

Location

Atrium Medical Center

Heerlen, Limburg, Netherlands

Location

Maastricht UMC+

Maastricht, Limburg, Netherlands

Location

Laurentius Ziekenhuis

Roermond, Limburg, Netherlands

Location

Orbis Medical Center

Sittard, Limburg, Netherlands

Location

VieCuri Medisch Centrum

Venlo, Limburg, Netherlands

Location

Jeroen Bosch Ziekenhuis

's-Hertogenbosch, North Brabant, Netherlands

Location

Bravis Ziekenhuis

Bergen op Zoom, North Brabant, Netherlands

Location

Amphia Ziekenhuis

Breda, North Brabant, Netherlands

Location

Elkerliek Ziekenhuis

Helmond, North Brabant, Netherlands

Location

Bravis Ziekenhuis

Roosendaal, North Brabant, Netherlands

Location

Sint Elisabeth Ziekenhuis

Tilburg, North Brabant, Netherlands

Location

TweeSteden Ziekenhuis

Tilburg, North Brabant, Netherlands

Location

Bernhoven

Uden, North Brabant, Netherlands

Location

Maxima Medisch Centrum, loc. Veldhoven

Veldhoven, North Brabant, Netherlands

Location

Medisch Centrum Alkmaar

Alkmaar, North Holland, Netherlands

Location

Amsterdam UMC, location AMC

Amsterdam, North Holland, 1105AZ, Netherlands

Location

Amsterdam UMC, location VUMC