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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Xu jianming, The Affiliated Hospital of the Chinese Academy of Military Medical Sciences
ClinicalTrials.gov Identifier:
NCT01523431
First received: January 19, 2012
Last updated: March 29, 2017
Last verified: March 2017

January 19, 2012
March 29, 2017
March 8, 2012
November 23, 2015   (Final data collection date for primary outcome measure)
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.
Association between UGT1A1 polymorphism and incidence of neutropenia and diarrhea [ Time Frame: From first 2 weeks to the whole treatment period, an expected average of 6 months ]
Incidence and grade of neutropenia and diarrhea are record in the whole treatment duration according to NCI-CTC AE 3.0 version
Complete list of historical versions of study NCT01523431 on ClinicalTrials.gov Archive Site
  • Response rate [ Time Frame: Every 6 weeks, an expected average of 6-8 months. ]
    Association between UGT1A1 polymorphism, CPT-11 dosage and tumor response.
  • 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.
  • 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).
  • Association between UGT1A1 polymorphism and irinotecan pharmacokinetics [ Time Frame: First 3 days from the treatment beginning ]
    Determine human plasma concentrations of irinotecan and its metabolites, SN-38, SN-38G, using high-performance liquid chromatography with fluorescence detector (HPLC-FLD)
  • Progression-free survival [ Time Frame: an expected average of 6 months ]
    PFS is defined as the length of time from randomise to disease progression of or to death from any cause other than progression.
  • Response rate [ Time Frame: every 6 weeks,an expected average of 6 months ]
    According to RECIST criteria
Not Provided
Not Provided
 
Individual Dosage Selection of Irinotecan (CPT-11) Based on UGT1A1 Genotype in Metastatic Colorectal Cancer Patients
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.

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.

Interventional
Phase 2
Phase 3
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: No masking
Primary Purpose: Treatment
Metastatic Colorectal Cancer
  • 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 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.
    Interventions:
    • Drug: Irinotecan Injection [Camptosar]
    • Drug: 5-fluorouracil
    • Drug: Leucovorin
  • 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.
    Interventions:
    • Drug: Irinotecan Injection [Camptosar]
    • Drug: 5-fluorouracil
    • Drug: Leucovorin
  • 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.
    Interventions:
    • Drug: Irinotecan Injection [Camptosar]
    • Drug: 5-fluorouracil
    • Drug: Leucovorin
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
583
April 27, 2016
November 23, 2015   (Final data collection date for primary outcome measure)

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.
Sexes Eligible for Study: All
18 Years and older   (Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
China
 
 
NCT01523431
MCRC-307PLAH-XJM
No
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
Not Provided
Not Provided
Xu jianming, The Affiliated Hospital of the Chinese Academy of Military Medical Sciences
The Affiliated Hospital of the Chinese Academy of Military Medical Sciences
Not Provided
Principal Investigator: Jian-Ming Xu, M.D. Affiliated Hospital, Academy of Military Medical Sciences
The Affiliated Hospital of the Chinese Academy of Military Medical Sciences
March 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP