Escalated Dose of Irinotecan in mCRC

Determination of the UGT1A1 Polymorphism as Guidance for Irinotecan Dose Escalation in Metastatic Colorectal Cancer Treated With First-Line Bevacizumab and FOLFIRI (PURE FIST)

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.

Study Overview

• Status: Completed
• Conditions: Metastatic Colorectal Cancer
• Intervention / Treatment: Genetic: UGT1A1 genotyping (6,6); Drug: bevacizumab (Avastin); Drug: irinotecan; Drug: Leucovorin; Drug: 5-FU; Genetic: UGTIA1 genotyping (6,7); Genetic: UGTIA1 genotyping (7,7); Genetic: UGT1A1 non-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.

• Study Type: Interventional
• Enrollment (Actual): 213
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Taiwan
  • Kaohsiung, Taiwan, 807
    • Chung-Ho Memorial Hospital, Kaohsiung Medical University:

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. 20 y/o ≦ Age ≦ 80y/o
2. Either metachronous or synchronous mCRC can be enrolled
3. Female patients need not ready to be pregnant or breastfeeding
4. No major underlying diseases (such as cardiovascular, cerebrovascular, malignant hypertension, kidney, liver and other major diseases)
5. mCRC be proven by pathologists or radiologists
6. Subjects are willing to sign an inform consent form

Exclusion Criteria:

• Patients who do not meet the including criteria or unwilling to participate

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: UGT1A1 genotyping (6,6); The investigators will escalate the dosage of irinotecan from 180mg/m2 to 260 mg/m2	Genetic: UGT1A1 genotyping (6,6); 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.; Other Names: UGT1A1*1*1; Drug: bevacizumab (Avastin); bevacizumab as target therapy; Other Names: Avastin; Drug: irinotecan; irinotecan as escalating dose according to UGT1A1 genotyping; Other Names: Campto; Drug: Leucovorin; combined with 5-FU; Drug: 5-FU; combined with irinotecan
Experimental: UGTA1T1 genotyping (6,7); The investigators will escalate the dosage of irinotecan from 180mg/m2 to 240 mg/m2	Drug: bevacizumab (Avastin); bevacizumab as target therapy; Other Names: Avastin; Drug: irinotecan; irinotecan as escalating dose according to UGT1A1 genotyping; Other Names: Campto; Drug: Leucovorin; combined with 5-FU; Drug: 5-FU; combined with irinotecan; Genetic: UGTIA1 genotyping (6,7); 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.; Other Names: UGT1A1*1*28
Experimental: UGTA1T1 genotyping (7,7); The investigators will escalate the dosage of irinotecan from 120mg/m2 to 180 mg/m2	Drug: bevacizumab (Avastin); bevacizumab as target therapy; Other Names: Avastin; Drug: irinotecan; irinotecan as escalating dose according to UGT1A1 genotyping; Other Names: Campto; Drug: Leucovorin; combined with 5-FU; Drug: 5-FU; combined with irinotecan; Genetic: UGTIA1 genotyping (7,7); 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.; Other Names: UGT1A1*28*28
Experimental: UGT1A1 non-genotyping; The investigators will maintain the dosage of irinotecan by 180mg/m2	Drug: bevacizumab (Avastin); bevacizumab as target therapy; Other Names: Avastin; Drug: irinotecan; irinotecan as escalating dose according to UGT1A1 genotyping; Other Names: Campto; Drug: Leucovorin; combined with 5-FU; Drug: 5-FU; combined with irinotecan; Genetic: UGT1A1 non-genotyping; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Progression-free survival	three to six months

Secondary Outcome Measures

Outcome Measure	Time Frame
Objective response rates	three to six months
overall survival	three to six months

Collaborators and Investigators

• Sponsor: Jaw-Yuan Wang, MD, PhD

Publications and helpful links

General Publications

• Tsai HL, Huang CW, Lin YW, Wang JH, Wu CC, Sung YC, Chen TL, Wang HM, Tang HC, Chen JB, Ke TW, Tsai CS, Huang HY, Wang JY. Determination of the UGT1A1 polymorphism as guidance for irinotecan dose escalation in metastatic colorectal cancer treated with first-line bevacizumab and FOLFIRI (PURE FIST). Eur J Cancer. 2020 Oct;138:19-29. doi: 10.1016/j.ejca.2020.05.031. Epub 2020 Aug 20.
• Yeh YS, Tsai HL, Huang CW, Wang JH, Lin YW, Tang HC, Sung YC, Wu CC, Lu CY, Wang JY. Prospective analysis of UGT1A1 promoter polymorphism for irinotecan dose escalation in metastatic colorectal cancer patients treated with bevacizumab plus FOLFIRI as the first-line setting: study protocol for a randomized controlled trial. Trials. 2016 Jan 25;17:46. doi: 10.1186/s13063-016-1153-3.

Study record dates

Study Major Dates

• Study Start (Actual): August 13, 2014
• Primary Completion (Actual): November 30, 2017
• Study Completion (Actual): November 30, 2017

Study Registration Dates

• First Submitted: September 18, 2014
• First Submitted That Met QC Criteria: October 3, 2014
• First Posted (Estimate): October 6, 2014

Study Record Updates

• Last Update Posted (Actual): November 17, 2021
• Last Update Submitted That Met QC Criteria: November 9, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protective Agents; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Micronutrients; Vitamins; Topoisomerase I Inhibitors; Antidotes; Vitamin B Complex; Bevacizumab; Leucovorin; Irinotecan
• Other Study ID Numbers: KMUHIRB-20130020