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

Colorectal Cancer Clinical Trial

— CAIRO5  

Official title:

Treatment Strategies in Colorectal Cancer Patients With Initially Unresectable Liver-only Metastases CAIRO5 a Randomized Phase 3 Study of the Dutch Colorectal Cancer Group (DCCG)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02162563
• Other study ID #: CAIRO5
• Secondary ID: 2013-005435-24
• Status: Recruiting
• Phase: Phase 3
• Start date: July 2014
• Est. completion date: July 2025

Study information

• Verified date: March 2022
• Source: Dutch Colorectal Cancer Group
• Contact: M.J.G. Bond, Drs.
• Phone: +31 6 20 58 16 94
• Email: m.j.g.bond-2[@]umcutrecht.nl
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 564
• Est. completion date: July 2025
• Est. primary completion date: August 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Colorectal Cancer
• Colorectal Neoplasms
• Liver Metastases
• Neoplasm Metastasis
• Neoplasms, Second Primary

Intervention

Drug:
• FOLFOX/ FOLFIRI with bevacizumab
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
• FOLFOXIRI with bevacizumab
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
• FOLFOX/ FOLFIRI with panitumumab
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

Locations

Country	Name	City	State
Belgium	Universitair ziekenhuis Antwerpen	Antwerpen
Netherlands	Jeroen Bosch Ziekenhuis	's Hertogenbosch	Noord-Brabant
Netherlands	Medisch Centrum Alkmaar	Alkmaar	Noord-Holland
Netherlands	Flevoziekenhuis	Almere	Flevoland
Netherlands	Meander Medisch Centrum	Amersfoort	Utrecht
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 Oost	Amsterdam	Noord-Holland
Netherlands	OLVG, locatie Oost	Amsterdam	Noord Holland
Netherlands	OLVG, locatie West	Amsterdam	Noord-Holland
Netherlands	Gelre Ziekenhuis	Apeldoorn	Gelderland
Netherlands	Rijnstate ziekenhuis	Arnhem	Gelderland
Netherlands	Wilhelmina Ziekenhuis	Assen	Drenthe
Netherlands	Bravis Ziekenhuis	Bergen op Zoom	Noord-Brabant
Netherlands	Rode Kruis Ziekenhuis	Beverwijk	Noord-Holland
Netherlands	Amphia Ziekenhuis	Breda	Noord-Brabant
Netherlands	Reinier de Graaf	Delft	Zuid-Holland
Netherlands	Hagaziekenhuis	Den Haag	Zuid-Holland
Netherlands	Medisch Centrum Haaglanden, Westeinde	Den Haag	Zuid-Holland
Netherlands	Deventer Ziekenhuis	Deventer	Overijssel
Netherlands	Albert Schweitzer Ziekenhuis	Dordrecht	Zuid-Holland
Netherlands	Ziekenhuis Nij Smellinghe	Drachten	Friesland
Netherlands	Gelderse Vallei	Ede	Gelderland
Netherlands	Catharina Ziekenhuis	Eindhoven	Noord-Brabant
Netherlands	Treant zorggroep	Emmen
Netherlands	Medisch Spectrum Twente	Enschede	Overijssel
Netherlands	St. Anna Ziekenhuis	Geldrop	Noord-Brabant
Netherlands	Admiraal de Ruyter ziekenhuis	Goes	Zeeland
Netherlands	Groene Hart Ziekenhuis	Gouda	Zuid-Holland
Netherlands	Martini Ziekenhuis	Groningen
Netherlands	UMC Groningen	Groningen
Netherlands	Spaarne Gasthuis	Haarlem	Noord-Holland
Netherlands	Sint Jansdal Ziekenhuis	Harderwijk	Gelderland
Netherlands	Atrium Medical Center	Heerlen	Limburg
Netherlands	Elkerliek Ziekenhuis	Helmond	Noord-Brabant
Netherlands	Ziekenhuisgroep Twente	Hengelo	Overijssel
Netherlands	Tergooi	Hilversum	Noord-Holland
Netherlands	Spaarne ziekenhuis	Hoofddorp	Noord-Holland
Netherlands	Bethesda ziekenhuis	Hoogeveen	Zuid Holland
Netherlands	Westfriesgasthuis	Hoorn	Noord-Holland
Netherlands	Medisch Centrum Leeuwarden, loc. Zuid	Leeuwarden	Friesland
Netherlands	LUMC	Leiden	Zuid-Holland
Netherlands	Maastricht UMC+	Maastricht	Limburg
Netherlands	Sint Antonius Ziekenhuis	Nieuwegein	Utrecht
Netherlands	Radboud UMC	Nijmegen	Gelderland
Netherlands	Waterlandziekenhuis	Purmerend	Noord-Holland
Netherlands	Laurentius Ziekenhuis	Roermond	Limburg
Netherlands	Bravis Ziekenhuis	Roosendaal	Noord-Brabant
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	Orbis Medical Center	Sittard	Limburg
Netherlands	Antonius Ziekenhuis	Sneek	Friesland
Netherlands	Sint Elisabeth Ziekenhuis	Tilburg	Noord-Brabant
Netherlands	TweeSteden Ziekenhuis	Tilburg	Noord-Brabant
Netherlands	Bernhoven	Uden	Noord-Brabant
Netherlands	UMC Utrecht	Utrecht	Zuid-Holland
Netherlands	Maxima Medisch Centrum, loc. Veldhoven	Veldhoven	Noord-Brabant
Netherlands	VieCuri Medisch Centrum	Venlo	Limburg
Netherlands	Streekziekenhuis Koningin Beatrix	Winterswijk	Gelderland
Netherlands	Zaans Medical Center	Zaandam	Noord-Holland
Netherlands	Isala Klinieken	Zwolle	Overijssel

Sponsors (1)

Lead Sponsor	Collaborator
Dutch Colorectal Cancer Group

Countries where clinical trial is conducted

Belgium,  Netherlands, 

Outcome

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

External Links

•   Website Dutch Colorectal Cancer Group