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Trial record 4 of 7 for:    ugt1a1 | Recruiting, Not yet recruiting, Available Studies | Interventional Studies | colorectal cancer | irinotecan

Prospective Analysis of UGT1A1 Promoter Polymorphism for Irinotecan Dose Escalation in Metastatic Colorectal Cancer Patients Treated With Bevacizumab Combined With FOLFIRI as the First-line Setting

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ClinicalTrials.gov Identifier: NCT02256800
Recruitment Status : Recruiting
First Posted : October 6, 2014
Last Update Posted : March 8, 2018
Sponsor:
Information provided by (Responsible Party):
Jaw-Yuan Wang, MD, PhD, Kaohsiung Medical University Chung-Ho Memorial Hospital

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.


Condition or disease Intervention/treatment Phase
Metastatic Colorectal Cancer Genetic: UGT1A1 genotyping (6,6) Genetic: UGTIA1 genotyping (6,7) Genetic: UGTIA1 genotyping (7,7) Genetic: UGT1A1 non-genotyping Drug: bevacizumab (Avastin) Drug: irinotecan Drug: Leucovorin Drug: 5-FU Not Applicable

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
Estimated Enrollment : 320 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Actual Study Start Date : August 13, 2013
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : December 31, 2018

Resource links provided by the National Library of Medicine

Drug Information available for: Irinotecan

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.


Drug: bevacizumab (Avastin)
Drug: irinotecan
Drug: Leucovorin
Drug: 5-FU
Experimental: UGTA1T1 genotyping (6,7)
The investigators will escalate the dosage of irinotecan from 180mg/m2 to 240 mg/m2
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.


Drug: bevacizumab (Avastin)
Drug: irinotecan
Drug: Leucovorin
Drug: 5-FU
Experimental: UGTA1T1 genotyping (7,7)
The investigators will escalate the dosage of irinotecan from 120mg/m2 to 180 mg/m2
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.


Drug: bevacizumab (Avastin)
Drug: irinotecan
Drug: Leucovorin
Drug: 5-FU
Experimental: UGT1A1 non-genotyping
The investigators will maintain the dosage of irinotecan by 180mg/m2
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.


Drug: bevacizumab (Avastin)
Drug: irinotecan
Drug: Leucovorin
Drug: 5-FU



Primary Outcome Measures :
  1. Progression-free survival [ Time Frame: three to six months ]

Secondary Outcome Measures :
  1. Objective response rates [ Time Frame: three to six months ]
  2. overall survival [ Time Frame: three to six months ]


Information from the National Library of Medicine

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Ages Eligible for Study:   20 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02256800


Locations
Taiwan
Chung-Ho Memorial Hospital, Kaohsiung Medical University: Recruiting
Kaohsiung, Taiwan, 807
Contact: Jaw-Yuan Wang, PhD       chunpin870132@yahoo.com.tw   
Principal Investigator: Jaw-Yuan Wang, Ph.D.         
Principal Investigator: Jaw-Yuan Wang, PhD         
Sponsors and Collaborators
Jaw-Yuan Wang, MD, PhD

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Jaw-Yuan Wang, MD, PhD, Professor, Kaohsiung Medical University Chung-Ho Memorial Hospital
ClinicalTrials.gov Identifier: NCT02256800     History of Changes
Other Study ID Numbers: KMUHIRB-20130020
First Posted: October 6, 2014    Key Record Dates
Last Update Posted: March 8, 2018
Last Verified: March 2018

Additional relevant MeSH terms:
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Irinotecan
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Bevacizumab
Camptothecin
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action