Individual Dosage Selection of Irinotecan (CPT-11) Based on UGT1A1 Genotype in Metastatic Colorectal Cancer Patients

March 29, 2017 updated by: Xu jianming, The Affiliated Hospital of the Chinese Academy of Military Medical Sciences

Influence of Individual Dosage Selection of Irinotecan (CPT-11) Based on UGT1A1 Genotype on Clinical Outcomes and Pharmacokinetics in Chinese Patients With Metastatic Colorectal Cancer

The purpose of this study is to investigate the influence of dose selection of CPT-11 on toxicity, response and pharmacokinetics according to UGT1A1 genotype in colorectal cancer patients.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Genetic polymorphisms of UGTs result in reduced enzyme activity and increased toxicity. UGT1A1*28 and UGT1A1*6 are reported to increase CPT-11-related toxicity in Asian patients. Moreover, the area under concentration curve (AUC) ratio of SN-38G to SN-38 is decreased in Asian patients having UGT1A1 *28 or UGT1A1*6. This implicated that the current standard dose of CPT-11 would be overdosing for homozygous UGT1A1*28/*28, *6/*6 or *28/*6 patients.

The study is designed to investigate the role of prospectively dose reduction of CPT-11 in toxicity, tumor response and pharmacokinetics for homozygous UGT1A1 patients, and compare these parameters to standard dose of CPT-11 for wild-type, heterozygous or homozygous UGT1A1 patients.

Study Type

Interventional

Enrollment (Actual)

583

Phase

  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • China
    • Beijing
      • Beijing, Beijing, China, 100071
        • Affiliated Hospital Cancer Center, Academy of Military Medical Sciences (307 Hospital of PLA)

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Histologically confirmed colorectal cancer patients who received no prior chemotherapy or failed to 1st line treatments
  2. At least one measurable lesion by Response Evaluation Criteria in Solid Tumors (RECIST) criteria
  3. Aged 18 years or older
  4. ECOG performance status of ≤ 2.
  5. Anticipated life expectancy of ≥ 3 months.
  6. UGT1A1 genotype tested. Categorized into Wild (UGT1A1*1/*1), Hetero (UGT1A1*1/ *28, UGT1A1*1/ *6), and Homo (UGT1A1*28/*28, UGT1A1*6/*6, UGT1A1*28/*6).

  7. Adequate organ function, including bone marrow, kidney and liver.

    • ANC ≥ 1.5×109/L and hemoglobin ≥ 9g/dL and platelet count ≥ 100×109/L
    • Serum total bilirubin ≤ 1.5 x ULN, alkaline phosphatase ≤ 2.5 x ULN, Serum ALT and AST ≤ 2.5 x ULN (Serum ALT and AST ≤ 5 x ULN, if liver metastases are present)
    • Serum creatinine ≤ 1.5 x ULN or CLcr > 60 ml/min
  8. Written informed consent can be obtained prior to their participation in the trial.

Exclusion Criteria:

  1. Pregnant or breast feeding women.
  2. Subjects who have previously received CPT-11 treatment.
  3. Serious concurrent complication, severe active infection.
  4. Subjects with chronic diarrhea, acute or sub acute Intestinal obstruction.
  5. Subjects with uncontrolled CNS metastasis or epilepsia or severe psychiatric disorders.
  6. Subjects who are regarded to be unsuitable for this trial by the investigator.
  7. Subjects who are participating in other clinical trials.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
ACTIVE_COMPARATOR: Standard FOLFIRI for wild/hetero UGT1A1
Irinotecan Injection [Camptosar] (CPT-11) 180 mg/m2, day 1; Leucovorin (LV) 400mg/m2, day 1; 5-fluorouracil (5-FU) 400mg/m2, day 1, 5-fluorouracil (5-FU) 2400mg/m2, day 1; Repeat every two weeks.
Drug: Irinotecan Injection [Camptosar]
CPT-11 will be administered according to UGT1A1 genotypes. Patients with UGT1A1 *1/*1 or heterozygous UGT1A1*1/*28 or *1/*6 will receive standard dose of CPT-11. Patients with homozygous UGT1A1*28/*28, *6/*6 or *28/*6, will be randomized in a 1:1 ratio to receive standard dose of CPT-11 or 50% reduced dose of CPT-11.
Other Names:
  • CPT-11
  • FOLFIRI regimen
Drug: 5-fluorouracil
The 5-FU dosage will remain the standard.
Other Names:
  • 5-FU
  • FOLFIRI regimen
Drug: Leucovorin
The LV dosage will remain the standard.
Other Names:
  • LV
  • FOLFIRI regimen
EXPERIMENTAL: Reduced Dose of CPT-11 for homo UGT1A1
Irinotecan Injection [Camptosar] (CPT-11) 90 mg/m2, day 1; Leucovorin (LV) 400mg/m2, day 1; 5-fluorouracil (5-FU) 400mg/m2, day 1, 5-fluorouracil (5-FU) 2400mg/m2, day 1; Repeat every two weeks.
Drug: Irinotecan Injection [Camptosar]
CPT-11 will be administered according to UGT1A1 genotypes. Patients with UGT1A1 *1/*1 or heterozygous UGT1A1*1/*28 or *1/*6 will receive standard dose of CPT-11. Patients with homozygous UGT1A1*28/*28, *6/*6 or *28/*6, will be randomized in a 1:1 ratio to receive standard dose of CPT-11 or 50% reduced dose of CPT-11.
Other Names:
  • CPT-11
  • FOLFIRI regimen
Drug: 5-fluorouracil
The 5-FU dosage will remain the standard.
Other Names:
  • 5-FU
  • FOLFIRI regimen
Drug: Leucovorin
The LV dosage will remain the standard.
Other Names:
  • LV
  • FOLFIRI regimen
ACTIVE_COMPARATOR: Standard FOLFIRI for homo UGT1A1
Irinotecan Injection [Camptosar] (CPT-11) 180 mg/m2, day 1; Leucovorin (LV) 400mg/m2, day 1; 5-fluorouracil (5-FU) 400mg/m2, day 1, 5-fluorouracil (5-FU) 2400mg/m2, day 1; Repeat every two weeks.
Drug: Irinotecan Injection [Camptosar]
CPT-11 will be administered according to UGT1A1 genotypes. Patients with UGT1A1 *1/*1 or heterozygous UGT1A1*1/*28 or *1/*6 will receive standard dose of CPT-11. Patients with homozygous UGT1A1*28/*28, *6/*6 or *28/*6, will be randomized in a 1:1 ratio to receive standard dose of CPT-11 or 50% reduced dose of CPT-11.
Other Names:
  • CPT-11
  • FOLFIRI regimen
Drug: 5-fluorouracil
The 5-FU dosage will remain the standard.
Other Names:
  • 5-FU
  • FOLFIRI regimen
Drug: Leucovorin
The LV dosage will remain the standard.
Other Names:
  • LV
  • FOLFIRI regimen

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of toxicity, especially neutropenia and diarrhea
Time Frame: From the beginning of treatment to the whole treatment period, an expected average of 6-8 months.
Association between UGT1A1 polymorphism, CPT-11 dosage and incidence of toxicity, especially neutropenia and diarrhea.
From the beginning of treatment to the whole treatment period, an expected average of 6-8 months.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Response rate
Time Frame: Every 6 weeks, an expected average of 6-8 months.
Association between UGT1A1 polymorphism, CPT-11 dosage and tumor response.
Every 6 weeks, an expected average of 6-8 months.
Progression-free survival (PFS)
Time Frame: An expected average of 6-8 months.
Association between UGT1A1 polymorphism, CPT-11 dosage and PFS. PFS is defined as the length of time from randomise to disease progression or to death from any cause other than progression.
An expected average of 6-8 months.
Pharmacokinetics of irinotecan and its metabolites, SN-38 and SN-38G.
Time Frame: The first treatment cycle.
Association between UGT1A1 polymorphism, CPT-11 dosage and pharmacokinetics of irinotecan. Plasma concentration of irinotecan and its metabolites, SN-38 and SN-38G are determined using high-performance liquid chromatography-tandem mass spectrometry method (HPLC-MS/MS).
The first treatment cycle.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

The Affiliated Hospital of the Chinese Academy of Military Medical Sciences

Investigators

  • Principal Investigator: Jian-Ming Xu, M.D., Affiliated Hospital, Academy of Military Medical Sciences

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

March 8, 2012

Primary Completion (ACTUAL)

November 23, 2015

Study Completion (ACTUAL)

April 27, 2016

Study Registration Dates

First Submitted

January 19, 2012

First Submitted That Met QC Criteria

January 29, 2012

First Posted (ESTIMATE)

February 1, 2012

Study Record Updates

Last Update Posted (ACTUAL)

March 30, 2017

Last Update Submitted That Met QC Criteria

March 29, 2017

Last Verified

March 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • MCRC-307PLAH-XJM

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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