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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
  Purpose
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.

Condition Intervention Phase
Metastatic Colorectal Cancer
Drug: Irinotecan Injection [Camptosar]
Drug: 5-fluorouracil
Drug: Leucovorin
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by The Affiliated Hospital of the Chinese Academy of Military Medical Sciences:

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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).


Enrollment: 583
Actual Study Start Date: March 8, 2012
Study Completion Date: April 27, 2016
Primary Completion Date: November 23, 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01523431

Locations
China, Beijing
Affiliated Hospital Cancer Center, Academy of Military Medical Sciences (307 Hospital of PLA)
Beijing, Beijing, China, 100071
Sponsors and Collaborators
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
  More Information

Responsible Party: Xu jianming, Director of Department of GI Cancer, The Affiliated Hospital of the Chinese Academy of Military Medical Sciences
ClinicalTrials.gov Identifier: NCT01523431     History of Changes
Other Study ID Numbers: MCRC-307PLAH-XJM
Study First Received: January 19, 2012
Last Updated: March 29, 2017

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

Keywords provided by The Affiliated Hospital of the Chinese Academy of Military Medical Sciences:
Colorectal cancer
Irinotecan
UGT1A1 genotype
Neutropenia
diarrhea
response
pharmacokinetic

Additional relevant MeSH terms:
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Irinotecan
Camptothecin
Fluorouracil
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antimetabolites
Antimetabolites, Antineoplastic
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on April 28, 2017