Escalated Dose of Irinotecan in mCRC
Condition: Metastatic Colorectal Cancer
MeSH terms: Colorectal Neoplasms
Study type: Interventional

Summary: 
      Metastatic diseases were found in 20-25% of patients with initial diagnosis of colorectal
      cancer and developed in up to 50% of patients. Owing to limited post-treatment response of
      5-fluorouracil (5-FU) combined with leucovorin (LV) obtained in mCRC (metastatic colorectal
      cancer) patients, other therapeutic agents with different mechanisms were considered, such as
      irinotecan, a potent inhibitor of topoisomerase I, which is involved in the unwinding of DNA
      during replication. Bevacizumab is a humanized monoclonal antibody that inhibits tumor
      angiogenesis by blocking vascular endothelial growth factor (VEGF) and was the first
      antiangiogenic agent approved for the treatment of cancer.

      Infusional fluorouracil/leucovorin plus irinotecan-based regimen (FOLFIRI) with bevacizumab
      has been widely used as first-line treatment for patients with metastatic colorectal cancer
      (mCRC). Recently, the investigators have shown that prospective analysis of uridine
      diphosphate glucuronosyl transferase 1A1 (UGT1A1) genotyping for irinotecan dose escalation
      (FOLFIRI regimen) with combination of bevacizumab biweekly as the first-line setting in mCRC
      patients (ASCO Abstract #491 - 2013 Gastrointestinal Cancers Symposium).

      In this study, the investigators will enroll approximately 320 mCRC patients (It was
      considered that an increase of response rate of 15% compared to conventional irinotecan dose
      of 180 mg/m2, and these were chosen as parameters with which to calculate the study power.
      Initial power calculation was suggested that a minimum of 140 patients in each group would be
      required to achieve statistical significance with a power of 80% at the 5% significance
      level. It is estimated that about 10% of 320 mCRC patients fail to complete the study). For
      these enrolled patients, the investigators will randomize and divide these patients into two
      groups: control group and study group. Control group includes mCRC patients who will receive
      the conventional regimen of FOLFIRI plus bevacizumab. Otherwise, patients in the study group
      will have genotyping of UGT1A1 before therapy, and dose escalating of irinotecan will depend
      on results of genotyping.
    

Detailed description: 
      Control group:

      Regimen for treatment consisted of bevacizumab (Avastin) 5mg/Kg (IV infusion) on day 1,
      follow by irinotecan (180 mg/m2 as a 120-min IV infusion), LV (400 mg/m2 IV infusion over 2
      hours), and 5-FU (2800 mg/m2 IV infusion over a 46-hour period), repeated every 2 weeks.

      Study group: FOLFIRI (infusional fluorouracil/leucovorin plus irinotecan) + Bevacizumab. The
      dosage of irinotecan is adjusted to the UGT1A1 genotyping

      The wild-type (6/6) of UGT1A1:

      Regimen for treatment consisted of bevacizumab (Avastin) 5mg/Kg (IV infusion) on day 1,
      follow by irinotecan (180 mg/m2 as a 120-min IV infusion), LV (400 mg/m2 IV infusion over 2
      hours), and 5-FU (2800 mg/m2 IV infusion over a 46-hour period), repeated every 2 weeks.

      After 2 cycles of each different dose of irinotecan, we will observe the adverse effects
      (AEs) of hematological / non-hematological. If the grade is under the grade 2, we will
      escalate the dose of 30 mg/m2 gradually. The estimated maximal dose of irinotecan is 260
      mg/m2.

      The (6,7) type of UGT1A1:

      Regimen for treatment consisted of bevacizumab (Avastin) 5mg/Kg (IV infusion) on day 1,
      follow by irinotecan (180 mg/m2 as a 120-min IV infusion), LV (400 mg/m2 IV infusion over 2
      hours), and 5-FU (2800 mg/m2 IV infusion over a 46-hour period), repeated every 2 weeks.

      After 2 cycles of each different dose of irinotecan, we will observe the adverse effects
      (AEs) of hematological / non-hematological. If the grade is under the grade 2, we will
      escalate the dose of 30 mg/m2 gradually. The estimated maximal dose of irinotecan is 240
      mg/m2.

      The (7,7) type of UGT1A1:

      Regimen for treatment consisted of bevacizumab (Avastin) 5mg/Kg (IV infusion) on day 1,
      follow by irinotecan (120 mg/m2 as a 120-min IV infusion), LV (400 mg/m2 IV infusion over 2
      hours), and 5-FU (2800 mg/m2 IV infusion over a 46-hour period), repeated every 2 weeks.

      After 2 cycles of each different dose of irinotecan, we will observe the adverse effects
      (AEs) of hematological / non-hematological. If the grade is under the grade 2, we will
      escalate the dose of 30 mg/m2 gradually. The estimated maximal dose of irinotecan is 180
      mg/m2.
    

Intervention name(s): UGT1A1 genotyping (6,6); UGTIA1 genotyping (6,7); UGTIA1 genotyping (7,7); UGT1A1 non-genotyping; bevacizumab (Avastin); irinotecan; Leucovorin; 5-FU
Intervention type(s): Genetic; Genetic; Genetic; Genetic; Drug; Drug; Drug; Drug
Intervention description(s): The investigators will use the regimen as following:
Regimen for treatment consisted of bevacizumab (Avastin) 5mg/Kg (IV infusion) on day 1, follow by irinotecan (180 mg/m2 as a 120-min IV infusion), Leucovorin (400 mg/m2 IV infusion over 2 hours), and 5-FU (2800 mg/m2 IV infusion over a 46-hour period), repeated every 2 weeks.
After 2 cycles of each different dose of irinotecan, we will observe the adverse effects (AEs) of hematological / non-hematological. If the grade is under the grade 2, we will escalate the dose of 30 mg/m2 gradually. The estimated maximal dose of irinotecan is 260 mg/m2.; The investigators will use the regimen as following:
Regimen for treatment consisted of bevacizumab (Avastin) 5mg/Kg (IV infusion) on day 1, follow by irinotecan (180 mg/m2 as a 120-min IV infusion), Leucovorin (400 mg/m2 IV infusion over 2 hours), and 5-FU (2800 mg/m2 IV infusion over a 46-hour period), repeated every 2 weeks.
After 2 cycles of each different dose of irinotecan, we will observe the adverse effects (AEs) of hematological / non-hematological. If the grade is under the grade 2, we will escalate the dose of 30 mg/m2 gradually. The estimated maximal dose of irinotecan is 240 mg/m2.; The investigators will use the regimen as following:
Regimen for treatment consisted of bevacizumab (Avastin) 5mg/Kg (IV infusion) on day 1, follow by irinotecan (120 mg/m2 as a 120-min IV infusion), Leucovorin (400 mg/m2 IV infusion over 2 hours), and 5-FU (2800 mg/m2 IV infusion over a 46-hour period), repeated every 2 weeks.
After 2 cycles of each different dose of irinotecan, we will observe the adverse effects (AEs) of hematological / non-hematological. If the grade is under the grade 2, we will escalate the dose of 30 mg/m2 gradually. The estimated maximal dose of irinotecan is 180 mg/m2.; The investigators will use the regimen as following:
Regimen for treatment consisted of bevacizumab (Avastin) 5mg/Kg (IV infusion) on day 1, follow by irinotecan (180 mg/m2 as a 120-min IV infusion), Leucovorin (400 mg/m2 IV infusion over 2 hours), and 5-FU (2800 mg/m2 IV infusion over a 46-hour period), repeated every 2 weeks.; bevacizumab as target therapy; irinotecan as escalating dose according to UGT1A1 genotyping; combined with 5-FU; combined with irinotecan
Other intervention name(s): UGT1A1*1*1; UGT1A1*1*28; UGT1A1*28*28; Avastin; Campto
Intervention MeSH terms: Leucovorin; Bevacizumab; Irinotecan
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment