Treatment Strategies in Colorectal Cancer Patients with Initially Unresectable Liver-only Metastases

Phase 3

Completed

• Conditions: Colorectal Cancer; Liver Metastases
• Interventions: Drug: FOLFOXIRI with bevacizumab; Drug: FOLFOX/ FOLFIRI with bevacizumab; Drug: FOLFOX/ FOLFIRI with panitumumab

• Registration Number: NCT02162563
• Lead Sponsor: Dutch Colorectal Cancer Group

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.

Detailed Description

Patients will be stratified for resectability of liver metastases (potentially resectable versus permanently unresectable), serum lactate dehydrogenase (LDH) (normal versus abnormal), BRAF mutation status (wildtype versus mutated), type of neoadjuvant chemotherapy (FOLFIRI versus FOLFOX) and hospital of registration.

Patients with RAS and BRAF wildtype and left-sided primary tumors will be randomised between FOLFOX or FOLFIRI plus either bevacizumab or panitumumab. The choice between FOLFOX or FOLFIRI is to the discretion of the local investigator, however, the treatment is restricted to regimens that are specified in the protocol. Patients with RAS or BRAF mutated and/or right-sided primary tumors will be randomized between FOLFOX/ FOLFIRI (investigator choice) plus bevacizumab or 5FU, irinotecan, oxaliplatin (FOLFOXIRI) plus bevacizumab.

Patients will be evaluated every 8 weeks by CT scan for disease status. The assigned systemic treatment should be continued for at least 6 months or earlier in case of resectability, progression of disease, unacceptable toxicity, or patient refusal. If after 6 months the panel concludes that the patient is still not resectable, it is highly unlikely that resectability will be achieved at all. Therefore the chemotherapy regimen may be reconsidered after 6 months of treatment. These patients should continue with the targeted drug in combination with chemotherapy, but the chemotherapy may be altered into a less toxic schedule such as fluoropyrimidine monotherapy. The targeted drug should be continued until progression or unacceptable toxicity. In patients who will become resectable and undergo secondary surgery of liver metastases, the total duration of preoperative and postoperative treatment together should be 6 months, with the chemotherapy schedule being administered according to the assigned treatment arm. However in these patients the targeted drug (bevacizumab or panitumumab) should not be continued after surgery.

Study Timeline

• Study First Submitted: 2014-06-05
• Study First Submitted QC: 2014-06-10
• Study First Posted: 2014-06-12
• Study Start: 2014-07
• Primary Completion: 2022-07
• Study Completion: 2025-01
• Status Verified: 2025-02
• Last Update Submitted: 2025-02-04
• Last Update Posted: 2025-02-06

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 530

Inclusion Criteria

• 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

Exclusion Criteria

• 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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm B: FOLFOXIRI & bevacizumab (inclusion completed)	FOLFOXIRI with bevacizumab	Patients with RAS or BRAF mutated and/or right-sided tumors will receive 5FU, irinotecan, oxaliplatin (FOLFOXIRI) and bevacizumab. Intervention: FOLFOXIRI with bevacizumab
Arm A: FOLFOX/FOLFIRI & bevacizumab (inclusion completed)	FOLFOX/ FOLFIRI with bevacizumab	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
Arm D: FOLFOX/FOLFIRI & panitumumab	FOLFOX/ FOLFIRI with panitumumab	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
Arm C: FOLFOX/ FOLFIRI & bevacizumab	FOLFOX/ FOLFIRI with bevacizumab	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

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
R0/1 secondary resection rate	2 years after last patient in study	R0/1 secondary resection rate in each of the 4 study arms upon neoadjuvant treatment with chemotherapy plus targeted therapy.
Median overall survival	8 years after last patient in study	From date of randomisation to death or last known to be alive
Toxicity (AE)	2 years after last patient in study	Patients will be evaluated for Adverse Events at the start of each treatment cycle according to CTCAE version 4.0.
Response rate	2 years after last patient in study	Response according to RECIST 1.1
Pathological complete response rate (pCR)	2 years after last patient in study	Pathological complete response rate (pCR) of the resected lesions
Postoperative morbidity	After surgery during two months	Patients will be evaluated for surgical morbidity during 2 months. Postoperative morbidity will be scored according 'Clavien Dindo Grade'.
Correlation of evaluation by the panel with outcome	2 years after last patient in study	CT-scans will be reviewed for liver resectability by expert panel before randomisation and during neo-adjuvant treatment (every 8 weeks).

Trial Locations

Locations (55)

Universitair ziekenhuis Antwerpen; 🇧🇪 Antwerpen, Belgium

Flevoziekenhuis; 🇳🇱 Almere, Flevoland, Netherlands

Ziekenhuis Nij Smellinghe; 🇳🇱 Drachten, Friesland, Netherlands

Medisch Centrum Leeuwarden, loc. Zuid; 🇳🇱 Leeuwarden, Friesland, Netherlands

Antonius Ziekenhuis; 🇳🇱 Sneek, Friesland, Netherlands

Gelre Ziekenhuis; 🇳🇱 Apeldoorn, Gelderland, Netherlands

Rijnstate ziekenhuis; 🇳🇱 Arnhem, Gelderland, Netherlands

Sint Jansdal Ziekenhuis; 🇳🇱 Harderwijk, Gelderland, Netherlands

Radboud UMC; 🇳🇱 Nijmegen, Gelderland, Netherlands

Streekziekenhuis Koningin Beatrix; 🇳🇱 Winterswijk, Gelderland, Netherlands

Atrium Medical Center; 🇳🇱 Heerlen, Limburg, Netherlands

Maastricht UMC+; 🇳🇱 Maastricht, Limburg, Netherlands

Laurentius Ziekenhuis; 🇳🇱 Roermond, Limburg, Netherlands

Orbis Medical Center; 🇳🇱 Sittard, Limburg, Netherlands

VieCuri Medisch Centrum; 🇳🇱 Venlo, Limburg, Netherlands

OLVG, locatie Oost; 🇳🇱 Amsterdam, Noord-Holland, Netherlands

Jeroen Bosch Ziekenhuis; 🇳🇱 's Hertogenbosch, Noord-Brabant, Netherlands

Bravis Ziekenhuis; 🇳🇱 Roosendaal, Noord-Brabant, Netherlands

Amphia Ziekenhuis; 🇳🇱 Breda, Noord-Brabant, Netherlands

Elkerliek Ziekenhuis; 🇳🇱 Helmond, Noord-Brabant, Netherlands

Sint Elisabeth Ziekenhuis; 🇳🇱 Tilburg, Noord-Brabant, Netherlands

TweeSteden Ziekenhuis; 🇳🇱 Tilburg, Noord-Brabant, Netherlands

Bernhoven; 🇳🇱 Uden, Noord-Brabant, Netherlands

Maxima Medisch Centrum, loc. Veldhoven; 🇳🇱 Veldhoven, Noord-Brabant, Netherlands

Medisch Centrum Alkmaar; 🇳🇱 Alkmaar, Noord-Holland, Netherlands

Amsterdam UMC, location AMC; 🇳🇱 Amsterdam, Noord-Holland, Netherlands

Amsterdam UMC, location VUMC; 🇳🇱 Amsterdam, Noord-Holland, Netherlands

Antoni van Leeuwenhoek; 🇳🇱 Amsterdam, Noord-Holland, Netherlands

BovenIJ Ziekenhuis; 🇳🇱 Amsterdam, Noord-Holland, Netherlands

OLVG, locatie West; 🇳🇱 Amsterdam, Noord-Holland, Netherlands

Spaarne Gasthuis; 🇳🇱 Haarlem, Noord-Holland, Netherlands

Tergooi; 🇳🇱 Hilversum, Noord-Holland, Netherlands

Spaarne ziekenhuis; 🇳🇱 Hoofddorp, Noord-Holland, Netherlands

Waterlandziekenhuis; 🇳🇱 Purmerend, Noord-Holland, Netherlands

Zaans Medical Center; 🇳🇱 Zaandam, Noord-Holland, Netherlands

Deventer Ziekenhuis; 🇳🇱 Deventer, Overijssel, Netherlands

Medisch Spectrum Twente; 🇳🇱 Enschede, Overijssel, Netherlands

Ziekenhuisgroep Twente; 🇳🇱 Hengelo, Overijssel, Netherlands

Isala Klinieken; 🇳🇱 Zwolle, Overijssel, Netherlands

Meander Medisch Centrum; 🇳🇱 Amersfoort, Utrecht, Netherlands

Sint Antonius Ziekenhuis; 🇳🇱 Nieuwegein, Utrecht, Netherlands

Admiraal de Ruyter ziekenhuis; 🇳🇱 Goes, Zeeland, Netherlands

Reinier de Graaf; 🇳🇱 Delft, Zuid-Holland, Netherlands

Hagaziekenhuis; 🇳🇱 Den Haag, Zuid-Holland, Netherlands

Medisch Centrum Haaglanden, Westeinde; 🇳🇱 Den Haag, Zuid-Holland, Netherlands

Albert Schweitzer Ziekenhuis; 🇳🇱 Dordrecht, Zuid-Holland, Netherlands

LUMC; 🇳🇱 Leiden, Zuid-Holland, Netherlands

Erasmus MC; 🇳🇱 Rotterdam, Zuid-Holland, Netherlands

Ikazia Ziekenhuis; 🇳🇱 Rotterdam, Zuid-Holland, Netherlands

Maasstad Ziekenhuis; 🇳🇱 Rotterdam, Zuid-Holland, Netherlands

Sint Franciscus Gasthuis; 🇳🇱 Rotterdam, Zuid-Holland, Netherlands

Franciscus Vlietland; 🇳🇱 Schiedam, Zuid-Holland, Netherlands

UMC Utrecht; 🇳🇱 Utrecht, Zuid-Holland, Netherlands

Martini Ziekenhuis; 🇳🇱 Groningen, Netherlands

UMC Groningen; 🇳🇱 Groningen, Netherlands