Escalated Dose of Irinotecan in mCRC

NCT02256800 | Completed

• 1 other identifier: KMUHIRB-20130020
• Study Type: interventional
• Target: 213
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Metastatic Colorectal Cancer

Outcome Measures

Primary Outcomes (1)

• Progression-free survival

  three to six months

Secondary Outcomes (2)

• Objective response rates

  three to six months

• overall survival

  three to six months

Study Arms (4)

UGT1A1 genotyping (6,6)

EXPERIMENTAL

The investigators will escalate the dosage of irinotecan from 180mg/m2 to 260 mg/m2

Genetic: UGT1A1 genotyping (6,6); Drug: bevacizumab (Avastin); Drug: irinotecan; Drug: Leucovorin; Drug: 5-FU

UGTA1T1 genotyping (6,7)

EXPERIMENTAL

The investigators will escalate the dosage of irinotecan from 180mg/m2 to 240 mg/m2

Genetic: UGTIA1 genotyping (6,7); Drug: bevacizumab (Avastin); Drug: irinotecan; Drug: Leucovorin; Drug: 5-FU

UGTA1T1 genotyping (7,7)

EXPERIMENTAL

The investigators will escalate the dosage of irinotecan from 120mg/m2 to 180 mg/m2

Genetic: UGTIA1 genotyping (7,7); Drug: bevacizumab (Avastin); Drug: irinotecan; Drug: Leucovorin; Drug: 5-FU

UGT1A1 non-genotyping

EXPERIMENTAL

The investigators will maintain the dosage of irinotecan by 180mg/m2

Genetic: UGT1A1 non-genotyping; Drug: bevacizumab (Avastin); Drug: irinotecan; Drug: Leucovorin; Drug: 5-FU

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.

Also known as: UGT1A1*1*1

UGT1A1 genotyping (6,6)

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.

Also known as: UGT1A1*1*28

UGTA1T1 genotyping (6,7)

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.

Also known as: UGT1A1*28*28

UGTA1T1 genotyping (7,7)

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.

UGT1A1 non-genotyping

bevacizumab (Avastin) DRUG

bevacizumab as target therapy

Also known as: Avastin

UGT1A1 genotyping (6,6); UGT1A1 non-genotyping; UGTA1T1 genotyping (6,7); UGTA1T1 genotyping (7,7)

irinotecan DRUG

irinotecan as escalating dose according to UGT1A1 genotyping

Also known as: Campto

UGT1A1 genotyping (6,6); UGT1A1 non-genotyping; UGTA1T1 genotyping (6,7); UGTA1T1 genotyping (7,7)

Leucovorin DRUG

combined with 5-FU

UGT1A1 genotyping (6,6); UGT1A1 non-genotyping; UGTA1T1 genotyping (6,7); UGTA1T1 genotyping (7,7)

5-FU DRUG

combined with irinotecan

UGT1A1 genotyping (6,6); UGT1A1 non-genotyping; UGTA1T1 genotyping (6,7); UGTA1T1 genotyping (7,7)

Eligibility Criteria

• Age: 20 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

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

Sponsors & Collaborators

• Jaw-Yuan Wang, MD, PhD: lead

Study Sites (1)

Chung-Ho Memorial Hospital, Kaohsiung Medical University:

Kaohsiung City, 807, Taiwan

Location

Related Publications (2)

• 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.

  PMID: 32829105 DERIVED

• 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.

  PMID: 26811156 DERIVED

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

UGT1A1 enzyme; Bevacizumab; Irinotecan; Leucovorin; Fluorouracil

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Camptothecin; Alkaloids; Heterocyclic Compounds; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Coenzymes; Enzymes and Coenzymes; Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: September 18, 2014
• First Posted: October 6, 2014
• Study Start: August 13, 2014
• Primary Completion: November 30, 2017
• Study Completion: November 30, 2017
• Last Updated: November 17, 2021

Record last verified: 2021-11

Locations

TW (1)