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

Metastatic Colorectal Cancer Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01523431
• Other study ID #: MCRC-307PLAH-XJM
• Status: Completed
• Phase: Phase 2/Phase 3
• First received: January 19, 2012
• Last updated: March 29, 2017
• Start date: March 8, 2012
• Est. completion date: April 27, 2016

Study information

• Verified date: March 2017
• Source: The Affiliated Hospital of the Chinese Academy of Military Medical Sciences
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 583
• Est. completion date: April 27, 2016
• Est. primary completion date: November 23, 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Colorectal Neoplasms
• Metastatic Colorectal Cancer

Intervention

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.
• 5-fluorouracil
The 5-FU dosage will remain the standard.
• Leucovorin
The LV dosage will remain the standard.

Locations

Country	Name	City	State
China	Affiliated Hospital Cancer Center, Academy of Military Medical Sciences (307 Hospital of PLA)	Beijing	Beijing

Sponsors (1)

Lead Sponsor	Collaborator
The Affiliated Hospital of the Chinese Academy of Military Medical Sciences

Country where clinical trial is conducted

China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of toxicity, especially neutropenia and diarrhea	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	Response rate	Association between UGT1A1 polymorphism, CPT-11 dosage and tumor response.	Every 6 weeks, an expected average of 6-8 months.
Secondary	Progression-free survival (PFS)	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.
Secondary	Pharmacokinetics of irinotecan and its metabolites, SN-38 and SN-38G.	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.