Escalated Dose of Irinotecan in mCRC

Sponsor
Jaw-Yuan Wang, MD, PhD
Study ID
NCT02256800
Status
Completed

Conditions

  • Metastatic Colorectal Cancer

Eligibility Criteria

Sex
ALL
Age
20 Years - 80 Years
Healthy Volunteers
Not accepted

Interventions

  • UGT1A1 genotyping (6,6) — GENETIC
    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.
  • UGTIA1 genotyping (6,7) — GENETIC
    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.
  • UGTIA1 genotyping (7,7) — GENETIC
    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.
  • UGT1A1 non-genotyping — GENETIC
    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 (Avastin) — DRUG
    bevacizumab as target therapy
  • irinotecan — DRUG
    irinotecan as escalating dose according to UGT1A1 genotyping
  • Leucovorin — DRUG
    combined with 5-FU
  • 5-FU — DRUG
    combined with irinotecan

Study Details

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.

Key Dates

Start date
Aug 13, 2014
Status verified
Nov 2021
Primary completion
Nov 30, 2017
Completion
Nov 30, 2017

Study Design

Enrollment
213 participants (actual)
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT

Arms

  • Experimental: UGT1A1 genotyping (6,6)
    The investigators will escalate the dosage of irinotecan from 180mg/m2 to 260 mg/m2
  • Experimental: UGTA1T1 genotyping (6,7)
    The investigators will escalate the dosage of irinotecan from 180mg/m2 to 240 mg/m2
  • Experimental: UGTA1T1 genotyping (7,7)
    The investigators will escalate the dosage of irinotecan from 120mg/m2 to 180 mg/m2
  • Experimental: UGT1A1 non-genotyping
    The investigators will maintain the dosage of irinotecan by 180mg/m2

Primary Outcome Measure

Progression-free survival [ Time Frame: three to six months ]

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