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

This study is currently recruiting participants.
Verified February 2013 by The Affiliated Hospital of the Chinese Academy of Military Medical Sciences
Sponsor:
Information provided by (Responsible Party):
The Affiliated Hospital of the Chinese Academy of Military Medical Sciences
ClinicalTrials.gov Identifier:
NCT01523431
First received: January 19, 2012
Last updated: February 26, 2013
Last verified: February 2013
History of Changes
  Purpose

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


Condition Intervention Phase
Metastatic Colorectal Cancer
 Drug: CPT-11
 Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Influence of Individual Dosage Selection of Irinotecan(CPT-11)Based on UGT1A1 Genotype on Pharmacokinetics and Clinical Outcome in Chinese Patients With Metastatic Colorectal Cancer

Resource links provided by NLM:

U.S. FDA Resources

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

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: Yes ]
    Incidence and grade of neutropenia and diarrhea are record in the whole treatment duration according to NCI-CTC AE 3.0 version


Secondary Outcome Measures:
  • Association between UGT1A1 polymorphism and irinotecan pharmacokinetics [ Time Frame: First 3 days from the treatment beginning ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    According to RECIST criteria


Estimated Enrollment: 500
Study Start Date: March 2012
Estimated Study Completion Date: September 2014
Estimated Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: homozygous UGT1A1*1
CPT-11(Irinotecan ) 180 mg/m2 90-minute i.v. infusion on day 1; leucovorin 400mg/m2 i.v. infusion on day 1 ; followed by 5-FU 400mg/m2 i.v. bolus on day 1, then 2400mg/m2 i.v. over 46 hours continuous infusion; repeat every two weeks.
 Drug: CPT-11
CPT-11 will be administered according to UGT1A1 genotypes, while the doses of infusional 5-FU/LV will remain the standard dose.
Other Name: irinotecan
Active Comparator: UGT1A1*1/*28 or UGT1A1*1/*6
CPT-11(Irinotecan ) 180 mg/m2 90-minute i.v. infusion on day 1; leucovorin 400mg/m2 i.v. infusion on day 1 ; followed by 5-FU 400mg/m2 i.v. bolus on day 1, then 2400mg/m2 i.v. over 46 hours continuous infusion; repeat every two weeks.
 Drug: CPT-11
CPT-11 will be administered according to UGT1A1 genotypes, while the doses of infusional 5-FU/LV will remain the standard dose.
Other Name: irinotecan
Experimental: UGT1A1*28/*28 or*6/ *6 or *28/*6
CPT-11(Irinotecan ) 90 mg/m2 90-minute i.v. infusion on day 1; leucovorin 400mg/m2 i.v. infusion on day 1 ; followed by 5-FU 400mg/m2 i.v. bolus on day 1, then 2400mg/m2 i.v. over 46 hours continuous infusion; repeat every two weeks.
 Drug: CPT-11
CPT-11 will be administered according to UGT1A1 genotypes, while the doses of infusional 5-FU/LV will remain the standard dose.
Other Name: irinotecan

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 UGT1A1 *28 or UGT1A1 *6 genotype patients.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
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
Please refer to this study by its ClinicalTrials.gov identifier: NCT01523431

Contacts
Contact: Xu jiangming, M.D. +861051128358 jmxu2003@yahoo.com
Contact: Wang yan, M.D. +861066947179 pretty.wy@163.com

Locations
China, Beijing
307 Hospital of PLA Recruiting
Beijing, Beijing, China, 100071
Contact: Xu jianming, M.D.     +861066947176     jmxu2003@yahoo.com    
Principal Investigator: Xu jianming, M.D.            
Sponsors and Collaborators
The Affiliated Hospital of the Chinese Academy of Military Medical Sciences
Investigators
Principal Investigator: Xu jianming, MD The Affiliated Hospital of the Chinese Academy of Military Medical Sciences
  More Information

No publications provided

Responsible Party: 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: February 26, 2013
Health Authority: China: Ethics Committee

Keywords provided by The Affiliated Hospital of the Chinese Academy of Military Medical Sciences:
Colorectal cancer
CPT-11
UGT1A1
Neutropenia
diarrhea

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
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Radiation-Sensitizing Agents
Physiological Effects of Drugs
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on May 23, 2013