Clinical trial NCT01523431: Individual Dosage Selection of Irinotecan (CPT-11) Based on UGT1A1 Genotype in Metastatic Colorectal Cancer Patients
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Metastatic Colorectal Cancer
Keywords: Colorectal cancer
Irinotecan
UGT1A1 genotype
Neutropenia
diarrhea
response
pharmacokinetic
Lead sponsor: The Affiliated Hospital of the Chinese Academy of Military Medical Sciences
Sponsor class: OTHER
First posted: 2012-02-01
Enrollment: 583
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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 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.

Primary outcomes:
measure: Incidence of toxicity, especially neutropenia and diarrhea
timeFrame: From the beginning of treatment to the whole treatment period, an expected average of 6-8 months.
Secondary outcomes:
measure: Response rate
timeFrame: Every 6 weeks, an expected average of 6-8 months.
measure: Progression-free survival (PFS)
timeFrame: An expected average of 6-8 months.
measure: Pharmacokinetics of irinotecan and its metabolites, SN-38 and SN-38G.
timeFrame: The first treatment cycle.
Other outcomes:
Locations:
city: Beijing
country: China
facility: Affiliated Hospital Cancer Center, Academy of Military Medical Sciences (307 Hospital of PLA)
state: Beijing
Study officials:
affiliation: Affiliated Hospital, Academy of Military Medical Sciences
name: Jian-Ming Xu, M.D.
role: PRINCIPAL_INVESTIGATOR
References: