UMIN-CTR Clinical Trial

Public title

Randomized phase ll study of mFOLFOX6 + bevacizumab or mFOLFOX6+cetuximab
in liver only metastasis from KRAS wild type colorectal cancer

Acronym

Achievement of improved survival by molecular Targeted chemotherapy and
liver resection for not Optimally resectable colorectal liver Metastases

Scientific Title

Randomized phase ll study of mFOLFOX6 + bevacizumab or mFOLFOX6+cetuximab
in liver only metastasis from KRAS wild type colorectal cancer

Scientific Title:Acronym

Achievement of improved survival by molecular Targeted chemotherapy and
liver resection for not Optimally resectable colorectal liver Metastases

Region

Japan

Condition

liver only metastasis from KRAS Exon 2 wild type (under protocol 1.0-1.2 edition) and RAS wild type (under protocol 2.0 edition) colorectal cancer

Classification by specialty

Medicine in general	Gastroenterology	Hepato-biliary-pancreatic medicine
Hematology and clinical oncology	Surgery in general	Gastrointestinal surgery
Hepato-biliary-pancreatic surgery

Classification by malignancy

Malignancy

Genomic information

NO

Narrative objectives1

To evaluate efficacy and safety of mFOLFOX6+bevacizumab and mFOLFOX6+cetuximab for liver only metastasis from KRAS Exon 2 wild type (under protocol 1.0-1.2 edition) and RAS wild type (under protocol 2.0 edition) colorectal cancer

Basic objectives2

Safety,Efficacy

Basic objectives -Others

Trial characteristics_1

Exploratory

Trial characteristics_2

Pragmatic

Developmental phase

Phase II

Primary outcomes

Progression-free survival (PFS); Central Review

Key secondary outcomes

-Response rate (RR)
-Tumor shrinkage rate at week 8
-Liver resection rate
-R0 liver resection rate (pathologically confirmed)
-Progression-free survival (PFS) ; CT/MRI image assessed by the attending investigator's
-Time to treatment-failure (TTF)
-Overall survival (OS)
-Incidence of adverse events (chemotherapy-related, surgery-related)
-Primary endpoint and secondary endpoints in the RAS wild type subpopulation

Study type

Interventional

Basic design

Parallel

Randomization

Randomized

Randomization unit

Individual

Blinding

Open -no one is blinded

Control

Uncontrolled

Stratification

YES

Dynamic allocation

YES

Institution consideration

Institution is not considered as adjustment factor.

Blocking

YES

Concealment

Central registration

No. of arms

2

Purpose of intervention

Treatment

Type of intervention

Medicine

Interventions/Control_1

mFOLFOX6 + bevacizumab

Interventions/Control_2

mFOLFOX6 + cetuximab

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

20

years-old

<=

Age-upper limit

80

years-old

>=

Gender

Male and Female

Key inclusion criteria

1.Histopathologically confirmed colorectal cancer (adenocarcinoma) excluding vermiform appendix cancer and proctos cancer.
2.RAS wild type
3.Synchronous* or metachronous liver limited meitastasis with no extrahepatic desiease
* shychronous liver limited metastasis with primary lesion less than two thirds of the circumference
* patients with primary lesion more than two thirds of the circumference can be enrolled after primary resection
4.Patients who has one or more lesion(s) of diameter 1 cm or larger (RECEST v1.1) be able to assesse continuously on the basis of the protocol by contrast enhanced CT or contrast enhanced MRI of the liver:
(1)Liver metastases 5 or more
(2)Liver metastases with 5 cm or larger in greatest dimension
(3)Unresectable considering remaining hepatic function
(4)Invasion into all hepatic veins or inferior vena cava
(5)Invasion into both right and left hepatic arteries or portal veins
5.No prior chemotherapy for colorectal cancer including hepatic arterial infusion. Excluding postoperative and preoperative chemoradiotherapy except for rectal cancer with synchronous liver metastases. Patients received postoperative chemotherapy containing oxaliplatin have to be enrolled after 24 weeks from the last oxaliplatin administration.
6.No previous treatment including ablation therapy, cryotherapy and chemotherapy for metastases
7.Age at enrollment is Full 20 or more years-old aged 80 and below
8.The Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1
9.Life expectancy from the day of enrollment is 3 months or longer
10.Major organ functions less than 14 days prior to entry meet the following criteria.
(1)Neu >= 1500/mm3
(2)Pt >= 10.0x104/mm3
(3)Hb >= 9.0 g/dL
(4)T-bil =< 2.0 mg/dL
(5)AST and ALT =< 200 IU/L
(6)sCr =< 1.20 mg/dL
(7)INR < 1.5
(8)Proteinuria =< 2+
11.Written informed consent

Key exclusion criteria

1.Previously experienced severe allergic reaction to drugs
2.Receiving anti-platelet drugs (aspirin >= 325 mg/day) or NSAIDs
3.Receiving chronic systemic corticosteroid treatment
4.Surgery/ biopsy with skin incision or traumatic injury with suture less than 14 days prior to entry. Excluding, suture for implanted venous reservoirs with catherter is allowed.
5.Severe postoperative complications (e.g. postoperative infection, anastomic dehiscence or paralytic ileus)
6.Diagnosed as hereditary colorectal cancer
7.Active other malignancies
8.Cerebrovascular disease or symptoms less than 1 year prior to entry
9.Pleural effusion, ascites or cardiac effusion requiring drainage
10.Hemorrhage/bleeding, paralytic ileus, obstruction or ulceration of gastrointestinal tract
11.Perforation of gastrointestinal tract less than 1 year prior to entry
12.Presence of active infection
13.HBs antigen or HCV antibody positive
14.Uncontrolled comorbidity including hypertension, diabetes, arrhythmia, or other diseases (such as cardiac disorder, interstitial pneumonia or renal disorder)
15.Presence of >= grade 2 diarrhea
16.Presence of >= grade 1 peripheral neuropathy
17.Pregnant or lactating women. Women and men with childbearing potential unwilling to use effective means of contraception
18.Psychosis or psychiatric symptoms who are not able to comply with the protocol
19.Any other medical conditions disable to comply with the protocol

Target sample size

120

Name of lead principal investigator

1st name
Middle name
Last name	Yoshihiko Maehara, Naohiro Tomita, Ichinosuke Hyodo, Michiaki Unno

Organization

Graduate School of Medical Science, Kyushu University
Hyogo College of Medicine
Graduate School of Comprehensive Human Sciences, Tsukuba University
Graduate School of Medicine, Tohoku University

Division name

Department of Surgery and Science/Department of Surgery/Department of Gastroenterology/Division of Gastroenterological Surgery

Zip code

Address

3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 Japan/1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501 Japan/2-1-1 Amakubo, Tsukuba 305-8576 Japan/1-1 Seiryo-cho, Aobaku, Sendai 980-8584 Japan

TEL

03-5684-7767

Email

prj-atomdc@eps.co.jp

Name of contact person

1st name
Middle name
Last name	Tatsumi Shimizu

Organization

EPS Corporation

Division name

Clinical Information Division Data Management Center

Zip code

Address

6-29 Shinogawamachi, Shinjuku-ku, Tokyo 162-0814 Japan

TEL

03-5684-7767

Homepage URL

Email

prj-atomdc@eps.co.jp

Institute

EPS Corporation

Institute

Department

Personal name

Organization

CHUGAI PARMACEUTICAL CO., LTD

Organization

Division

Category of Funding Organization

Profit organization

Nationality of Funding Organization

Co-sponsor

Name of secondary funder(s)

Organization

Address

Tel

Email

Secondary IDs

YES

Study ID_1

NCT01836653

Org. issuing International ID_1

ClinicalTrials.gov

Study ID_2

Org. issuing International ID_2

IND to MHLW

Institutions

<北海道>
函館五稜郭病院
北海道大学病院
市立札幌病院
釧路労災病院
NTT東日本札幌病院
<青森>
弘前大学医学部附属病院
<岩手>
岩手医科大学
<宮城>
石巻赤十字病院
東北大学病院
宮城県立がんセンター
東北労災病院
<秋田>
大曲厚生医療センター
<山形>
公立置賜総合病院
<福島>
いわき市立総合磐城共立病院
<茨城>
日立総合病院
土浦協同病院
茨城県立中央病院
筑波大学附属病院
水戸医療センター
<群馬>
群馬県立がんセンター
<千葉>
帝京大学ちば総合医療センター
千葉県がんセンター
成田赤十字病院
国保旭中央病院
<東京>
東邦大学医療センター大森病院
東京医科歯科大学医学部附属病院
東京女子医科大学
都立駒込病院
国立国際医療研究センター病院
<神奈川>
横須賀市立うわまち病院
相模原病院
昭和大学藤が丘病院
横浜市立大学附属病院
昭和大学横浜市北部病院
<新潟>
新潟県立がんセンター新潟病院
<富山>
富山県立中央病院
<石川>
金沢赤十字病院
石川県立中央病院
<福井>
福井県済生会病院
福井県立病院
福井大学医学部附属病院
福井病院
<岐阜>
朝日大学歯学部附属村上記念病院
松波総合病院
岐阜大学
<静岡>
聖隷浜松病院
浜松医療センター
<愛知>
名古屋市立大学
愛知県がんセンター中央病院
名古屋医療センター
半田市立半田病院
<三重>
三重大学医学部附属病院
<滋賀>
滋賀県立成人病センター
大津市民病院
<京都>
京都桂病院
京都大学医学部附属病院
<大阪>
大阪医科大学附属病院
近畿大学
済生会中津病院
<兵庫>
佐野病院
神戸医療センター
姫路赤十字病院
兵庫医科大学
兵庫県立淡路医療センター
神戸市立医療センター中央市民病院
神戸大学
西神戸医療センター
兵庫県立西宮病院
明和病院
<岡山>
岡山大学病院
<広島>
中国中央病院
県立広島病院
広島大学
広島赤十字原爆病院
<山口>
下関医療センター
山口大学医学部附属病院
<徳島>
徳島大学病院
<香川>
香川大学医学部附属病院
<愛媛>
四国がんセンター
松山赤十字病院
<福岡>
久留米大学
飯塚病院
九州中央病院
久留米大学医療センター
済生会福岡総合病院
JCHO九州病院
九州大学
九州医療センター
北九州総合病院
九州がんセンター
製鉄記念八幡病院
<佐賀>
佐賀大学医学部附属病院
<長崎>
佐世保市立総合病院
長崎大学
<熊本>
熊本大学
済生会熊本病院
<大分>
別府医療センター
大分赤十字病院
<鹿児島>
鹿児島大学
<沖縄>
中頭病院
那覇市立病院
琉球大学医学部附属病院

Date of disclosure of the study information

2013

Year

03

Month

13

Day

URL releasing protocol

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738101/bin/41416_2019_518_MOESM2_ESM.pdf

Publication of results

Published

URL related to results and publications

https://www.nature.com/articles/s41416-019-0518-2

Number of participants that the trial has enrolled

122

Results

On March 31, 2017, the median follow-up time was 24.3 months. The median PFS assessed by the IRC for the CET arm was 14.8 months (95% confidence interval (CI): 9.7-17.3 months), while for the BEV arm it was 11.5 months (95% CI: 9.2-13.3 months), with a log-rank P value of 0.33. The PFS HR between the two arms was 0.803 (95% CI: 0.513-1.25)

Results date posted

2021

Year

02

Month

27

Day

Results Delayed

Results Delay Reason

Date of the first journal publication of results

Baseline Characteristics

Between May 2013 and April 2016, we enrolled 122 patients from 63 sites in Japan (61 patients in each arm).

Participant flow

5 patients (2 CET arm/3 BEV arm) did not meet the criteria and a patient in the BEV arm cannot be treated because of rapid disease progression.
116 patients (BEV group: 57 patients, CET group: 59 patients) were included in the efficacy and safety analysis.

Adverse events

Grade =>3 subjective or objective toxicity events occurred in 40.4% of the patients who received BEV and 52.5% of the patients who received CET. The most frequently occurring AE of grade =>3 was neutropenia, with an incidence of 36.8% in the BEV arm and 50.8% in the CET arm.
AEs that caused discontinuation occurred in 8 patients (13.1%) in the BEV arm and 6 (9.8%) in the CET arm. No patient died from treatment-related AEs.
In the surgical safety population (n = 33 in the BEV arm and n = 29 in the CET arm), all-grade surgery-related AEs according to the Clavien-Dindo classification were reported in 8 patients (24.2%) in the BEV arm and 12 (41.4%) in the CET arm. The most frequent surgical AE was bile leakage, with an incidence of 18.2% in the BEV arm and 24.1% in the CET arm. No grade 5 AEs were reported.

Outcome measures

Progression free survival(PFS)

Plan to share IPD

IPD sharing Plan description

Recruitment status

Completed

Date of protocol fixation

2013

Year

03

Month

05

Day

Date of IRB

2013

Year

02

Month

28

Day

Anticipated trial start date

2013

Year

05

Month

07

Day

Last follow-up date

2017

Year

03

Month

31

Day

Date of closure to data entry

2017

Year

04

Month

30

Day

Date trial data considered complete

2017

Year

06

Month

30

Day

Date analysis concluded

Other related information

Registered date

2013

Year

03

Month

11

Day

Last modified on

2021

Year

03

Month

01

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000011957