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Treatment Strategies in Colorectal Cancer Patients With Initially Unresectable Liver-only Metastases (CAIRO5)

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ClinicalTrials.gov Identifier: NCT02162563
Recruitment Status : Recruiting
First Posted : June 12, 2014
Last Update Posted : October 13, 2017
Sponsor:
Information provided by (Responsible Party):
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.


Condition or disease Intervention/treatment Phase
Colorectal Cancer Liver Metastases Drug: FOLFOX/ FOLFIRI with bevacizumab Drug: FOLFOXIRI with bevacizumab Drug: FOLFOX/ FOLFIRI with panitumumab Phase 3

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 Type : Interventional  (Clinical Trial)
Estimated Enrollment : 564 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Study Start Date : July 2014
Estimated Primary Completion Date : July 2020
Estimated Study Completion Date : July 2025

Resource links provided by the National Library of Medicine

Drug Information available for: Bevacizumab

Arm Intervention/treatment
Experimental: Arm B: FOLFOXIRI & bevacizumab

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
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
Other Names:
  • - bevacizumab
  • - irinotecan
  • - oxaliplatin
  • - leucovorin
  • - 5-fluorouracil

Active Comparator: Arm A: FOLFOX/FOLFIRI & 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

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

Other Names:
  • - bevacizumab
  • - irinotecan
  • - leucovorin
  • - 5-fluorouracil
  • - oxaliplatin

Experimental: Arm D: FOLFOX/FOLFIRI & 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

Drug: 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

Other Names:
  • - panitumumab
  • - irinotecan
  • - leucovorin
  • - 5-fluorouracil
  • - oxaliplatin

Active Comparator: Arm C: FOLFOX/ FOLFIRI & 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

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

Other Names:
  • - bevacizumab
  • - irinotecan
  • - leucovorin
  • - 5-fluorouracil
  • - oxaliplatin




Primary Outcome Measures :
  1. Progression-free survival (PFS) [ Time Frame: 2 years after last patient in study ]
    Time from registration until progression or death whichever comes first


Secondary Outcome Measures :
  1. R0/1 secondary resection rate [ Time Frame: 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.

  2. Median overall survival [ Time Frame: 8 years after last patient in study ]
    From date of randomisation to death or last known to be alive

  3. Response rate [ Time Frame: 2 years after last patient in study ]
    Response according to RECIST 1.1

  4. Toxicity (AE) [ Time Frame: 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.

  5. Pathological complete response rate (pCR) [ Time Frame: 2 years after last patient in study ]
    Pathological complete response rate (pCR) of the resected lesions

  6. Postoperative morbidity [ Time Frame: After surgery during two months ]
    Patients will be evaluated for surgical morbidity during 2 months. Postoperative morbidity will be scored according 'Clavien Dindo Grade'.

  7. Correlation of evaluation by the panel with outcome [ Time Frame: 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).



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically proven colorectal cancer
  • Unresectable metastases confined to the liver according to CT scan, obtained ≤ 2 weeks prior to registration. Unresectability will be confirmed by the panel. Patients with small (≤ 1 cm) extrahepatic lesions that are not clearly suspicious of metastases are eligible.
  • Adequate tumor tissue available for assessment of RAS/BRAF mutation status
  • 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 ³ 6.0 mmol/L, absolute neutrophil count ³ 1.5 x 109/L, platelets ³ 100 x 109/L), renal function (serum creatinine ≤ 1.5x ULN and creatinine clearance, Cockroft formula, ³ 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 lesionsthat 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 registration
  • 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 registration
  • 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
  • Any concomitant experimental treatment.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02162563


Contacts
Contact: K. Bolhuis, Drs. +31 20 5665568 k.bolhuis@amc.uva.nl
Contact: B. Hemmes, PhD +31 617806051 b.hemmes@iknl.nl

  Show 65 Study Locations
Sponsors and Collaborators
Dutch Colorectal Cancer Group
Investigators
Principal Investigator: C.J.A. Punt, Prof. dr. Academic Medical Center, Amsterdam NL
Principal Investigator: T.M. van Gulik, Prof. dr. Academic Medical Center, Amsterdam NL

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Dutch Colorectal Cancer Group
ClinicalTrials.gov Identifier: NCT02162563     History of Changes
Other Study ID Numbers: CAIRO5
2013-005435-24 ( EudraCT Number )
First Posted: June 12, 2014    Key Record Dates
Last Update Posted: October 13, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by Dutch Colorectal Cancer Group:
Colorectal cancer
Chemotherapy
Anti-EGFR
Liver metastases
R0 R1 liver resection
Resectability of liver
Liver expert panel

Additional relevant MeSH terms:
Colorectal Neoplasms
Neoplasm Metastasis
Neoplasms, Second Primary
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Neoplastic Processes
Pathologic Processes
Bevacizumab
Oxaliplatin
Irinotecan
Camptothecin
Fluorouracil
Leucovorin
Antibodies, Monoclonal
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Topoisomerase I Inhibitors