UMIN-CTR Clinical Trial

Public title

Genetic Polymorphism oriented PhaseI Study of Irinotecan and Doxifluridine for Unresectable or Recurrent Colorectal Cancer

Acronym

Genetic Polymorphism oriented PhaseI Study of Irinotecan and Doxifluridine for metastatic Colorectal Cancer

Scientific Title

Genetic Polymorphism oriented PhaseI Study of Irinotecan and Doxifluridine for Unresectable or Recurrent Colorectal Cancer

Scientific Title:Acronym

Genetic Polymorphism oriented PhaseI Study of Irinotecan and Doxifluridine for metastatic Colorectal Cancer

Region

Japan

Condition

colorectal cancer

Classification by specialty

Gastroenterology

Gastrointestinal surgery

Classification by malignancy

Malignancy

Genomic information

YES

Narrative objectives1

The aim of this study is to confirm the RD of irinotecan when combined with a fluoropyrimidine in patients with advanced colorectal cancer.

Basic objectives2

Safety

Basic objectives -Others

Trial characteristics_1

Trial characteristics_2

Developmental phase

Primary outcomes

Primary endpoint: MTD, DLT, recomended dose

Key secondary outcomes

Study type

Interventional

Basic design

Single arm

Randomization

Non-randomized

Randomization unit

Blinding

Open -no one is blinded

Control

Uncontrolled

Stratification

Dynamic allocation

Institution consideration

Blocking

Concealment

No. of arms

1

Purpose of intervention

Treatment

Type of intervention

Medicine

Gene

Interventions/Control_1

Patients received treatment for 12 weeks. CPT-11 was administered once every two weeks in 500 ml of normal saline or dextrose via 120-min intravenous infusion on day 1, 15, 29, 43, 57 and 71. 5-DFUR was given as 200-mg capsules, two capsules were administered orally in the morning and evening after a meal on 5 consecutive days followed by a 2-day washout during the 12-week treatment period.

Interventions/Control_2

Interventions/Control_3

Interventions/Control_4

Interventions/Control_5

Interventions/Control_6

Interventions/Control_7

Interventions/Control_8

Interventions/Control_9

Interventions/Control_10

Age-lower limit

15

years-old

<=

Age-upper limit

75

years-old

>=

Gender

Male and Female

Key inclusion criteria

Patients were eligible for this study if they met the following criteria: proven unresectable or recurrent colorectal cancer; age between 20 and 75 years; no major surgery, radiotherapy or chemotherapy within 4 weeks prior to the study; Eastern Cooperative Oncology Group performance status of 0 to 2;predicted life expectancy of at least 3 months; adequate baseline organ functions, defined as a leukocyte count of at least 4,000/uL, neutrophil count of at least 2,000/uL, platelet count of at least 100,000/uL, hemoglobin of at least 9.0 g/dL, AST and ALT of 3 times or less the upper limit of the institutional reference range; total bilirubin below 1.5 mg/dL, and serum creatinine below 1.5 mg/dL.

Key exclusion criteria

Patients were ineligible if they had any of the following conditions: serious infectious disease or other severe complications (e.g., pulmonary fibrosis/interstitial pneumonia, uncontrollable diabetes); watery diarrhea, paralytic ileus, or intestinal obstruction; massive pleural effusion or ascitic fluid; symptomatic brain metastases; active concurrent malignancies; pregnancy or lactation, or desire for pregnancy; a history of drug allergy; and prior treatment with CPT-11.

Target sample size

18

Name of lead principal investigator

1st name
Middle name
Last name	Masaaki Oka

Organization

Yamaguchi University Graduate School of Medicine

Division name

Department of Digestive Surgery and Surgical Oncology (Surgery II)

Zip code

Address

1-1-1 Minami-kogushi, Ube, Yamaguchi 755-8505, JAPAN

TEL

Email

Name of contact person

1st name
Middle name
Last name	Shoichi Hazama

Organization

Yamaguchi University Graduate School of Medicine

Division name

Department of Digestive Surgery and Surgical Oncology (Surgery II)

Zip code

Address

TEL

Homepage URL

Email

hazama@yamaguchi-u.ac.jp

Institute

Department of Digestive Surgery and Surgical Oncology (Surgery II), and Department of Oncology and Laboratory Medicine, Yamaguchi University Graduate School of Medicine

Institute

Department

Personal name

Organization

Department of Oncology and Laboratory Medicine, Yamaguchi University Graduate School of Medicine

Organization

Division

Category of Funding Organization

Self funding

Nationality of Funding Organization

Co-sponsor

Name of secondary funder(s)

Organization

Address

Tel

Email

Secondary IDs

NO

Study ID_1

Org. issuing International ID_1

Study ID_2

Org. issuing International ID_2

IND to MHLW

Institutions

Date of disclosure of the study information

2009

Year

06

Month

18

Day

URL releasing protocol

Publication of results

Published

URL related to results and publications

Number of participants that the trial has enrolled

Results

Although individuals carrying the UGT1A1 allele *28 have an
increased risk of severe toxicities associated with irinotecan, no
phase I study has been conducted based on the polymorphism. This
report presents the recommended doses of irinotecan for patients
with the respective genotypes. Twenty-seven patients with
advanced colorectal cancer were enrolled in this study, and the
UGT1A1*28 polymorphism was genotyped before chemotherapy.
One course of chemotherapy consisted of irinotecan infused once
every 2 weeks at 70, 100, 120, and 150 mg⁄m2 at dose levels 1, 2, 3,
and 4, respectively, and doxifluridine was administered orally. This
treatment continued for at least 12 weeks. The dose-limiting toxicity
was determined as grade 3 hematological and non-hematological
toxicities for the TA6 ⁄ TA6 (6 ⁄ 6) and TA6 ⁄ TA7 (6 ⁄ 7) genotypes.
The pharmacokinetics of irinotecan, SN-38, and SN-38 glucuronide,
was assessed at dose level 2. Eighteen and nine patients had the
6 ⁄ 6 and 6 ⁄ 7 genotypes, respectively. The maximum tolerated dose
(MTD) was not observed up to dose level 4 in patients with the 6 ⁄ 6
genotype. In contrast, MTD was observed at dose level 2
(100 mg⁄m2) in patients with the 6 ⁄ 7 genotype. Patients with the
6 ⁄ 7 genotype had a significantly higher area under the plasma
time–concentration curve 0-\ SN-38 (P = 0.022) and biliary index
(P = 0.030) than those with 6 ⁄ 6. The recommended starting doses
of biweekly irinotecan for phase II ⁄ III were 150 mg⁄m2 for patients
with the UGT1A1 6 ⁄ 6 genotype and 70 mg⁄m2 for those with the
6 ⁄ 7 genotype, respectively. The gene polymorphism should be considered
when determining the precise recommended doses to be
administered in phase I studies. (Cancer Sci 2010; 101: 722-727)

Results date posted

Results Delayed

Results Delay Reason

Date of the first journal publication of results

Baseline Characteristics

Participant flow

Adverse events

Outcome measures

Plan to share IPD

IPD sharing Plan description

Recruitment status

Completed

Date of protocol fixation

2004

Year

12

Month

20

Day

Date of IRB

Anticipated trial start date

2005

Year

01

Month

01

Day

Last follow-up date

2009

Year

12

Month

01

Day

Date of closure to data entry

2009

Year

12

Month

01

Day

Date trial data considered complete

2009

Year

12

Month

01

Day

Date analysis concluded

2009

Year

12

Month

01

Day

Other related information

Registered date

2009

Year

06

Month

18

Day

Last modified on

2010

Year

07

Month

21

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000002554