Clinical Trials /

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

NCT02162563

Description:

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.

Related Conditions:
  • Colorectal Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Treatment Strategies in Colorectal Cancer Patients With Initially Unresectable Liver-only Metastases
  • 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 IDs

  • ORG STUDY ID: CAIRO5
  • SECONDARY ID: 2013-005435-24
  • NCT ID: NCT02162563

Conditions

  • Colorectal Cancer
  • Liver Metastases

Interventions

DrugSynonymsArms
FOLFOX/ FOLFIRI with bevacizumab- bevacizumab, - irinotecan, - leucovorin, - 5-fluorouracil, - oxaliplatinArm A: FOLFOX/FOLFIRI & bevacizumab
FOLFOXIRI with bevacizumab- bevacizumab, - irinotecan, - oxaliplatin, - leucovorin, - 5-fluorouracilArm B: FOLFOXIRI & bevacizumab
FOLFOX/ FOLFIRI with panitumumab- panitumumab, - irinotecan, - leucovorin, - 5-fluorouracil, - oxaliplatinArm D: FOLFOX/FOLFIRI & panitumumab

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm B: FOLFOXIRI & bevacizumabExperimentalPatients with RAS or BRAF mutated and/or right-sided tumors will receive 5FU, irinotecan, oxaliplatin (FOLFOXIRI) and bevacizumab. Intervention: FOLFOXIRI with bevacizumab
  • FOLFOXIRI with bevacizumab
Arm A: FOLFOX/FOLFIRI & bevacizumabActive ComparatorPatients 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
  • FOLFOX/ FOLFIRI with bevacizumab
Arm D: FOLFOX/FOLFIRI & panitumumabExperimentalPatients 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
  • FOLFOX/ FOLFIRI with panitumumab
Arm C: FOLFOX/ FOLFIRI & bevacizumabActive ComparatorPatients 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
  • FOLFOX/ FOLFIRI with bevacizumab

Eligibility Criteria

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

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

Secondary Outcome Measures

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

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Dutch Colorectal Cancer Group

Trial Keywords

  • Colorectal cancer
  • Chemotherapy
  • Anti-EGFR
  • Liver metastases
  • R0 R1 liver resection
  • Resectability of liver
  • Liver expert panel

Last Updated

February 15, 2019