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

Primary Purpose

Metastatic Colorectal Cancer

Status

Completed

Phase

Phase 2

Locations

China

Study Type

Interventional

Intervention

Irinotecan Injection [Camptosar]

5-fluorouracil

Leucovorin

About this trial

This is an interventional treatment trial for Metastatic Colorectal Cancer focused on measuring Colorectal cancer, Irinotecan, UGT1A1 genotype, Neutropenia, diarrhea, response, pharmacokinetic

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Histologically confirmed colorectal cancer patients who received no prior chemotherapy or failed to 1st line treatments
At least one measurable lesion by Response Evaluation Criteria in Solid Tumors (RECIST) criteria
Aged 18 years or older
ECOG performance status of ≤ 2.
Anticipated life expectancy of ≥ 3 months.
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).
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
Written informed consent can be obtained prior to their participation in the trial.

Exclusion Criteria:

Pregnant or breast feeding women.
Subjects who have previously received CPT-11 treatment.
Serious concurrent complication, severe active infection.
Subjects with chronic diarrhea, acute or sub acute Intestinal obstruction.
Subjects with uncontrolled CNS metastasis or epilepsia or severe psychiatric disorders.
Subjects who are regarded to be unsuitable for this trial by the investigator.
Subjects who are participating in other clinical trials.

Sites / Locations

Affiliated Hospital Cancer Center, Academy of Military Medical Sciences (307 Hospital of PLA)

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Experimental

Active Comparator

Arm Label

Standard FOLFIRI for wild/hetero UGT1A1

Reduced Dose of CPT-11 for homo UGT1A1

Standard FOLFIRI for homo UGT1A1

Arm Description

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.

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.

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.

Outcomes

Primary Outcome Measures

Incidence of toxicity, especially neutropenia and diarrhea

Association between UGT1A1 polymorphism, CPT-11 dosage and incidence of toxicity, especially neutropenia and diarrhea.

Secondary Outcome Measures

Response rate

Association between UGT1A1 polymorphism, CPT-11 dosage and tumor response.

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.

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).

Full Information

NCT ID

NCT01523431

First Posted

January 19, 2012

Last Updated

March 29, 2017

Sponsor

The Affiliated Hospital of the Chinese Academy of Military Medical Sciences

1. Study Identification

Unique Protocol Identification Number

NCT01523431

Brief Title

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

2. Study Status

Record Verification Date

March 2017

Overall Recruitment Status

Completed

Study Start Date

March 8, 2012 (Actual)

Primary Completion Date

November 23, 2015 (Actual)

Study Completion Date

April 27, 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

The Affiliated Hospital of the Chinese Academy of Military Medical Sciences

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Metastatic Colorectal Cancer

Keywords

Colorectal cancer, Irinotecan, UGT1A1 genotype, Neutropenia, diarrhea, response, pharmacokinetic

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2, Phase 3

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

583 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Standard FOLFIRI for wild/hetero UGT1A1

Arm Type

Active Comparator

Arm Description

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.

Arm Title

Reduced Dose of CPT-11 for homo UGT1A1

Arm Type

Experimental

Arm Description

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.

Arm Title

Standard FOLFIRI for homo UGT1A1

Arm Type

Active Comparator

Arm Description

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.

Intervention Type

Drug

Intervention Name(s)

Irinotecan Injection [Camptosar]

Other Intervention Name(s)

CPT-11, FOLFIRI regimen

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

5-fluorouracil

Other Intervention Name(s)

5-FU, FOLFIRI regimen

Intervention Description

The 5-FU dosage will remain the standard.

Intervention Type

Drug

Intervention Name(s)

Leucovorin

Other Intervention Name(s)

LV, FOLFIRI regimen

Intervention Description

The LV dosage will remain the standard.

Primary Outcome Measure Information:

Title

Incidence of toxicity, especially neutropenia and diarrhea

Description

Association between UGT1A1 polymorphism, CPT-11 dosage and 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.

Secondary Outcome Measure Information:

Title

Response rate

Description

Association between UGT1A1 polymorphism, CPT-11 dosage and tumor response.

Time Frame

Every 6 weeks, an expected average of 6-8 months.

Title

Progression-free survival (PFS)

Description

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.

Time Frame

An expected average of 6-8 months.

Title

Pharmacokinetics of irinotecan and its metabolites, SN-38 and SN-38G.

Description

Time Frame

The first treatment cycle.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Histologically confirmed colorectal cancer patients who received no prior chemotherapy or failed to 1st line treatments At least one measurable lesion by Response Evaluation Criteria in Solid Tumors (RECIST) criteria Aged 18 years or older ECOG performance status of ≤ 2. Anticipated life expectancy of ≥ 3 months. 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). 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 Written informed consent can be obtained prior to their participation in the trial. Exclusion Criteria: Pregnant or breast feeding women. Subjects who have previously received CPT-11 treatment. Serious concurrent complication, severe active infection. Subjects with chronic diarrhea, acute or sub acute Intestinal obstruction. Subjects with uncontrolled CNS metastasis or epilepsia or severe psychiatric disorders. Subjects who are regarded to be unsuitable for this trial by the investigator. Subjects who are participating in other clinical trials.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Jian-Ming Xu, M.D.

Organizational Affiliation

Affiliated Hospital, Academy of Military Medical Sciences

Official's Role

Principal Investigator

Facility Information:

Facility Name

Affiliated Hospital Cancer Center, Academy of Military Medical Sciences (307 Hospital of PLA)

City

Beijing

State/Province

Beijing

ZIP/Postal Code

100071

Country

China

12. IPD Sharing Statement

Learn more about this trial

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

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