UMIN-CTR Clinical Trial

Public title

A randomized phase II study to investigate the deepness of response of FOLFOXIRI plus cetuximab (Erbitux) versus FOLFOXIRI plus bevacizumab as the first-line therapy in metastatic colorectal cancer patients with RAS wild-type tumors: DEEPER

Acronym

JACCRO CC-13 study

Scientific Title

A randomized phase II study to investigate the deepness of response of FOLFOXIRI plus cetuximab (Erbitux) versus FOLFOXIRI plus bevacizumab as the first-line therapy in metastatic colorectal cancer patients with RAS wild-type tumors: DEEPER

Scientific Title:Acronym

JACCRO CC-13 study

Region

Japan

Condition

Measurable advanced colorectal cancer with RAS wild-type ( KRAS exon 2,3,4; NRAS exon 2,3,4)

Classification by specialty

Gastroenterology

Gastrointestinal surgery

Classification by malignancy

Malignancy

Genomic information

YES

Narrative objectives1

To verify the advantage of FOLFOXIRI plus cetuximab against FOLFOXIRI plus bevacizumab as the first-line therapy in advanced colorectal cancer patients with RAS wild-type tumors

Basic objectives2

Safety,Efficacy

Basic objectives -Others

Trial characteristics_1

Exploratory

Trial characteristics_2

Pragmatic

Developmental phase

Phase II

Primary outcomes

DpR: Deepness of Response

Key secondary outcomes

ETS: Early Tumor shrinkage
RR: Response Rate
DpR: Deepness of Response (at 4 weeks)
TTF: Time to Treatment Failure
TTG: Time to Tumor Growth
PFS: Progression-Free Survival
OS: Overall Survival
Correlation between tumor shrinkage(ETS, RR, DpR) and prognosis(PFS, OS)
Correlation between TTG and OS
Resection rate
R0 resection rate
Safety

Study type

Interventional

Basic design

Parallel

Randomization

Randomized

Randomization unit

Individual

Blinding

Open -no one is blinded

Control

Active

Stratification

YES

Dynamic allocation

YES

Institution consideration

Institution is considered as adjustment factor in dynamic allocation.

Blocking

NO

Concealment

Central registration

No. of arms

2

Purpose of intervention

Treatment

Type of intervention

Medicine

Interventions/Control_1

FOLFOXIRI+Bevacizumab (until 12 courses)
5-FU+Levofolinate+Bevacizumab (after 13 courses)

Bevacizumab 5mg/kg/bi-weekly
Irinotecan 150mg/m2/bi-weekly
Oxaliplatin 85mg/m2/bi-weekly
Levofolinate 200mg/m2/bi-weekly
5-FU 2400mg/m2/bi-weekly

Interventions/Control_2

FOLFOXIRI+Cetuximab (until 12 courses)
5-FU+Levofolinate+etuximab (after 13 courses)

Cetuximab (first time) 400 mg/m2/week
Cetuximab (after 2nd time) 250 mg/m2/week
Irinotecan 150mg/m2/bi-weekly
Oxaliplatin 85mg/m2/bi-weekly
Levofolinate 200mg/m2/bi-weekly
5-FU 2400mg/m2/bi-weekly

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

Not applicable

Gender

Male and Female

Key inclusion criteria

(1) Histologically confirmed colorectal cancer.
(2) RAS wild-type.
(3) Measurable leision by RECIST.(Ver.1.1)
(4) No past history of chemotherapy in the case of unresectable primary lesion/distant metastasis/lymph node metastasis.In the case of recurrence, no treatment for the first recurrence leision after operation.
(5) Age; more than 20 years old.
(6) ECOG Performance status 0-1.The case >=71 years is PS0.
(7) Life expectancy of more than 6 months.
(8) Patiens have enough organ function for study treatment within 14 days before enrollment;
1) WBC>=3,000/mm3, <12,000/mm3.
2) Neu>=1,500/mm3.
3) PLT>=10.0x104/mm3.
4) Hb>=9.0g/dL.
5) Total Bilirubin<=1.5xULN.
6) AST<=2.5xULN.
7) ALT<=2.5xULN.
8) Creatinine<=1.5xULN.
9) Proteinuria<=1+.
10) PT-INR<=1.5.
(9) Written informed consent.

Key exclusion criteria

(1) Synchronous multiple malignancy or metachronous multiple malignancy within 5 years disease free interval. (2) Suspicious of Lynch syndrome (3) Brain metastases. (4) Infectious disease. (5) Interstitial lung disease or pulmonary fibrosis. (6) Comorbidity or history of serious heart failure. (7) History of thromboembolic events. (8) Cerebrovascular disease. (9) History of hemoptysis/hematemesis. (10) Uncontrolled hypertension.(systolic BP>180mmHg, or diastolic BP>100mmHg) (11) Sensory alteration or paresthesia interfering with function. (12) Large quantity of pleural, abdominal or cardiac effusion. (13) Severe comorbidity (renal failure, liver failure, hypertension, etc) (14) Prior radiotherapy for primary and metastases leision. (15) Men/women who are unwilling to avoid pregnancy. Women who are pregnant or breastfeeding. Women with a positive pregnancy test. (16) History of severe allergy. (17) HBsAg positive or active viral hepatitis. (18) Administration of blood products/ G-CSF, and blood transfusion within 14 days. (19) Surgical procedure or such as skin-open biopy, trauma surgery, or other more intensive surgeries within 28 days. (20) Systemaic administration of antiplatelet drug or NSAIDs. (21) Diathesis of bleeding (history of hemoptysis, including cavitation and/or necrosis in lung metastasis confirmed by imaging), coagulopathy. (22) History of gastrointestinal perforation within 1 year. (23) Unhealed traumatic bone fracture. (24) Uncontrolled diarrhea. (25) History of organ recipient . (26) Prior cetuximab/bevacizumab/Irinotecan/Oxaliplatin treatment.(Adjuvant therapy by Oxaliplatin is excluded) (27) Administration of atazanavir sulfate. (28) Jaundice. (29) Ileus or bowel obstruction. (30) Any other cases who are regarded as inadequate for study enrollment by investigators.

Target sample size

360

Name of lead principal investigator

1st name	Akihito
Middle name
Last name	Tsuji

Organization

Faculty of Medicine, Kagawa University

Division name

Department of Clinical Oncology

Zip code

761-0793

Address

1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan

TEL

087-898-5111

Email

atsuji@med.kagawa-u.ac.jp

Name of contact person

1st name	Masashi
Middle name
Last name	Fujii

Organization

Japan Clinical Cancer Reseach Organization (JACCRO)

Division name

Research Office

Zip code

101-0051

Address

6F Jimbocho Kyowa Bldg, 1-64-3 Kanda-Jimbocho, Chiyoda-ku, Tokyo

TEL

03-6811-0433

Homepage URL

Email

cc13.dc@jaccro.or.jp

Institute

Japan Clinical Cancer Reseach Organization (JACCRO)

Institute

Department

Personal name

Organization

Merck Serono Co., Ltd.

Organization

Division

Category of Funding Organization

Profit organization

Nationality of Funding Organization

Co-sponsor

Name of secondary funder(s)

Organization

Japan Clinical Cancer Reseach Organization (JACCRO)

Address

6F Jimbocho Kyowa Bldg, 1-64-3 Kanda-Jimbocho, Chiyoda-ku, Tokyo

Tel

03-6811-0433

Email

jaccro@jaccro.or.jp

Secondary IDs

YES

Study ID_1

jRCTs061180022

Org. issuing International ID_1

Japan Registry of Clinical Trials

Study ID_2

Org. issuing International ID_2

IND to MHLW

Institutions

香川大学医学部附属病院（香川県）他

Date of disclosure of the study information

2015

Year

07

Month

15

Day

URL releasing protocol

https://jrct.mhlw.go.jp/latest-detail/jRCTs061180022

Publication of results

Published

URL related to results and publications

https://jrct.mhlw.go.jp/latest-detail/jRCTs061180022

Number of participants that the trial has enrolled

359

Results

Our study demonstrated that FOLFOXIRI + cetuximab had clinical benefit for tumor shrinkage in mCRC patients with RAS wild-type tumors compared to FOLFOXIRI + bevacizumab, with manageable safety.
Furthermore, this study suggests that FOLFOXIRI plus cetuximab regimen may be a good option for initial therapy with longer survival time in RAS/BRAF wild-type and left-sided mCRC pts, specially with extra-hepatic metastases or male patients.

Results date posted

2025

Year

05

Month

30

Day

Results Delayed

Results Delay Reason

Date of the first journal publication of results

Baseline Characteristics

Baseline characteristics of the PPS were below. The median age at the time of informed consent was 65 years (cetuximab arm: 65 years; bevacizumab arm: 65 years). Approximately 64.5% were men (cetuximab arm: 63.5%; bevacizumab arm: 65.4%). ECOG PS was 0 in 91.0% (cetuximab arm: 91.8%; bevacizumab arm: 90.1%). The primary tumor located on the left side in 83.8% (cetuximab arm: 83.0%; bevacizumab arm: 84.6%).

Participant flow

Between 1 July 2015 and 30 June 2019, 359 patients with RAS wild-type, unresectable mCRC were randomly assigned to receive FOLFOXIRI + cetuximab (n=179) or FOLFOXIRI + bevacizumab (n=180). Overall, 351 patients received at least one dose of study treatment and were included in the safety population (cetuximab arm: n=175; bevacizumab arm: n=176). In the per protocol set (PPS) cohort, 159 and 162 patients were included in the cetuximab and bevacizumab arm, respectively.

Adverse events

One patient in the bevacizumab arm died of acute myocardial infarction, and two patients in the cetuximab arm died of disseminated intravascular coagulation, which were judged as treatment-related deaths.
The incidence of Grade 1 or higher adverse events was 99.4% in the cetuximab arm and 100% in the bevacizumab arm. The most common Grade 3 or higher adverse events were neutropenia (cetuximab arm: 56.0%; bevacizumab arm: 54.5%), hypertension (cetuximab arm: 17.7%; bevacizumab arm: 33.5%), anorexia (cetuximab arm: 12.0%; bevacizumab arm: 10.8%) and diarrhea (cetuximab arm: 12.0%; bevacizumab arm: 8.8%).

Outcome measures

The primary endpoint, median DpR by the central review board was 57.3% in the cetuximab arm and 46.0% in the bevacizumab arm, p=0.0029 by t-test, indicating statistically significant favorable tumor reduction. Objective response rate was 71.1% (95% CI: 64.0-78.1) in the cetuximab arm and 69.1% (95% CI: 62.0-76.2) in the bevacizumab arm. R0 resection rate was 26.4% (95%CI: 19.6-33.3) in the cetuximab arm and 21.0% (95%CI: 14.7-27.3) in the bevacizumab arm.
After the 5-year follow-up, median PFS was 13.0 months (95% CI: 11.3-14.5) in the cetuximab group and 12.3 months (95% CI: 11.3-14.0) in the bevacizumab group (p=0.2914, hazard ratio: 0.884). Median OS was 41.7 months (95% CI: 34.9-49.0) in the cetuximab group and 41.6 months (95% CI: 33.9-46.7) in the bevacizumab group (p=0.5199, Hazard Ratio: 0.920).
Analysis using BRAF mutation information from the JACCRO CC-13AR study, in 178 patients with BRAF wild-type and left-sided patients, median PFS was 14.8 months in the cetuximab arm and 11.9 months in the bevacizumab arm (p=0.0285, hazard ratio: 0.710) and median OS was 50.2 months in the cetuximab arm and 40.2 months in the bevacizumab arm (p=0.0911, hazard ratio: 0.743). The exploratory analysis by clinical factors showed that cetuximab arm had longer PFS and OS in BRAF wild type and left-sided patients with extra-hepatic metastases. In addition, median OS was better in the cetuximab arm among male patients.

Plan to share IPD

IPD sharing Plan description

Recruitment status

Completed

Date of protocol fixation

2015

Year

06

Month

23

Day

Date of IRB

2015

Year

06

Month

23

Day

Anticipated trial start date

2015

Year

07

Month

15

Day

Last follow-up date

2022

Year

07

Month

01

Day

Date of closure to data entry

Date trial data considered complete

Date analysis concluded

Other related information

Registered date

2015

Year

07

Month

06

Day

Last modified on

2025

Year

05

Month

30

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000021085