UMIN-CTR Clinical Trial

Public title

A Randomized, Multicenter, Phase III Study to Compare 6 Months of either 5-Fluorouracil / l-leucovorin plus Oxaliplatin (mFOLFOX6) or Capecitabine plus Oxaliplatin (XELOX) with 3 Months of either mFOLFOX6 or XELOX as Adjuvant Chemotherapy in Patients with Completely Resected Stage III Colon Cancer

Acronym

Adjuvant Chemotherapy for colon cancer with HIgh EVidencE
(JFMC47-1202-C3: ACHIEVE Trial)

Scientific Title

A Randomized, Multicenter, Phase III Study to Compare 6 Months of either 5-Fluorouracil / l-leucovorin plus Oxaliplatin (mFOLFOX6) or Capecitabine plus Oxaliplatin (XELOX) with 3 Months of either mFOLFOX6 or XELOX as Adjuvant Chemotherapy in Patients with Completely Resected Stage III Colon Cancer

Scientific Title:Acronym

Adjuvant Chemotherapy for colon cancer with HIgh EVidencE
(JFMC47-1202-C3: ACHIEVE Trial)

Region

Japan

Condition

stage III colon cancer (including rectosigmoid cancer)

Classification by specialty

Gastroenterology	Hematology and clinical oncology	Gastrointestinal surgery
Hepato-biliary-pancreatic surgery

Classification by malignancy

Malignancy

Genomic information

YES

Narrative objectives1

To evaluate the non-inferiority of treatment with mFOLFOX6/XELOX for 3 months as adjuvant chemotherapy versus 6 months of mFOLFOX6/ XELOX in terms of disease-free survival by IDEA pooled analysis for curatively resected stage III colon cancer (including rectosigmoid cancer).

Basic objectives2

Efficacy

Basic objectives -Others

Trial characteristics_1

Confirmatory

Trial characteristics_2

Pragmatic

Developmental phase

Phase III

Primary outcomes

Disease-free survival*1
*1: DFS is defined as relapse or death by IDEA.

Key secondary outcomes

(1) Disease-free survival*2
*2: DFS is defined as relapse, second cancer or death.
(2) Time to treatment failure
(3) Overall survival
(4) Adverse events
(5) Completion rate
(6) Relative dose intensity
(7) Peripheral neuropathy
(8) Lymph node metastasis, lymph node dissection, lymph nodes examined, and prognosis
(9) Exploration of prognostic indicators and adverse events
(Additional study: Pharmacogenomics).

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

YES

Concealment

Central registration

No. of arms

2

Purpose of intervention

Treatment

Type of intervention

Medicine

Interventions/Control_1

Standard Arm (six months)

(1)mFOLFOX6 (12 courses)
L-OHP 85mg/m2
l-LV 200mg/m2
5-FU 400mg/m2 (bolus)
5-FU 2400mg/m2 (infusion)
every 2weeks

(2)XELOX (8 courses)
Oxaliplatin 130mg/m2 day1
Capacitabine 2000 or 1500mg/m2 day1 - 15(bid)
every 3 weeks

Interventions/Control_2

Test Arm (three months)

(1)mFOLFOX6 (6 courses)
L-OHP 85mg/m2
l-LV 200mg/m2
5-FU 400mg/m2 (bolus)
5-FU 2400mg/m2 (infusion)
every 2weeks

(2)XELOX (4 courses)
Oxaliplatin 130mg/m2 day1
Capacitabine 2000 or 1500mg/m2 day1 - 15(bid)
every 3 weeks

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 adenocarcinoma of the colon.
(2) Predominantly located in the cecum, colon, or rectosigmoid region based on the findings from surgery and/or surgical specimen.
(3) D2 or D3 lymph nodes resection.
(4) Curability A surgery (no residual tumor visible to macroscopically and/or microscopically).
(5) Stage III (T any N1/2/3 M0) (cf. The Japanese Classification of Colorectal Carcinoma, 7th edition, revised version).
(6) Registration within 8 weeks after resection and chemotherapy starting within 2 weeks after registration.
(7) Age >= 20 years.
(8) ECOG performance status of 0-1.
(9) Body surface area (DuBois) <=2.2 m2.
(10) No prior chemotherapy, immunotherapy, or radiation therapy.
(11) Adequate organ function:
i) neutrophil count >=1,500/mm3
ii) platelet count >=100,000/mm3
iii) serum creatinine <=1.5 times the ULN
iv) CCr >=30mL/min
v) total bilirubin <=2.0 mg/dL
vi) AST and ALT <=100 IU/L
vii) CEA <=10 ng/mL
(12) Written informed consent.

Key exclusion criteria

(1) Cancer of the appendix.
(2) Past history of malignancy. (When there is the unrecurred period of 5 or more years, the intramucosal carcinoma [stomach cancer, colorectal cancer, esophagus cancer] by which recovery excision was performed endoscopically, the uterine cervical cancer, the basal cell carcinoma of the skin, and squamous cell carcinoma of the skin by which curative excision was performed can be enrolled.)
(3) Women who are pregnant or breast-feeding.
(4) Women who may become pregnant and fertile men.
(5) Participation in another clinical trial within 30 days before registration.
(6) Existing grade 1 or more peripheral sensory neuropathy.
(7) Uncontrolled diabetes mellitus (including insulin therapy).
(8) Uncontrolled congestive heart failure, angina pectoris, hypertension, and/or arrhythmia.
(9) Continuous systemic steroid therapy (oral or intravenous administration).
(10) A history and/or current evidence of significant neurological and/or mental illness.
(11) Active infectious disease (including known active hepatitis B virus infection, hepatitis C virus infection and human immunodeficiency virus).
(12) Known dihydropyrimidine dehydrogenase (DPD) deficiency.
(13) A history of allergy to 5-FU, l-LV, oxaliplatin, and/or capecitabine.
(14) Prior chemotherapy including oxaliplatin.
(15) Other reasons for being unfit for the study as determined by the attending physician.

Target sample size

1200

Name of lead principal investigator

1st name	Masaki(1),Atsushi(2),Takayuki(3)
Middle name
Last name	Mori(1),Ohtsu(2),Yoshino(3)

Organization

Osaka University Graduate School of Medicine(1),National Cancer Center Hospital East(2),(3)

Division name

Department of Gastroenterological Surgery(1),Research Center for Innovative Oncology(2),Department of Gastrointestinal Oncology(3)

Zip code

565-0871

Address

2-2-E2 Yamadaoka, Suita, Osaka 565-0871 Japan(1),6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577 Japan(2),(3)

TEL

03-5627-7594

Email

jfmc47@jfmc.or.jp

Name of contact person

1st name	Japanese Foundation for Multidisciplinary Treatmen
Middle name
Last name	Japanese Foundation for Multidisciplinary Treatment of Cancer

Organization

Japanese Foundation for Multidisciplinary Treatment of Cancer

Division name

Office

Zip code

136-0071

Address

1-28-6 kameido, koutou-ku, Tokyo, 136-0071 Japan

TEL

03-5627-7594

Homepage URL

http://www.jfmc.or.jp/

Email

jfmc-dc@jfmc.or.jp

Institute

Japanese Foundation for Multidisciplinary Treatment of Cancer

Institute

Department

Personal name

Organization

Yakult Honsha Co., Ltd.

Organization

Division

Category of Funding Organization

Profit organization

Nationality of Funding Organization

Co-sponsor

Name of secondary funder(s)

Organization

National Cancer Center Hospital East

Address

6-5-1 Kashiwanoha, Kashiwa city, Chiba

Tel

04-7133-1111

Email

ncche-irb@east.ncc.go.jp

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

2012

Year

08

Month

01

Day

URL releasing protocol

https://www.jfmc.or.jp/ex/wp-content/uploads/2015/01/jfmc47_1202_c3.pdf

Publication of results

Published

URL related to results and publications

https://ascopubs.org/doi/10.1200/JCO.21.02628

Number of participants that the trial has enrolled

1291

Results

Median follow-up period was 6.2 years.

1. OS
The 5-year survival was 86.4% in 6-month arm(6M) and 87.0% in 3-month arm(3M), hazard ratio (HR, 3M/6M 95% CI) was 0.91 (0.69-1.20), p = 0.5112 (Log-rank). Three months of XELOX might be the most appropriate treatment option in patients with low-risk stage III colon cancer.

2. DFS
The 5-year DFS was 74.2% in 6M and 75.2% in 3M, HR (3M/6M 95% CI) was 0.95 (0.77-1.18), p = 0.6418 (Log-rank). In subgroup analysis, a tendency is similar to OS.

Results date posted

2022

Year

06

Month

22

Day

Results Delayed

Results Delay Reason

Date of the first journal publication of results

Baseline Characteristics

Modified ITT (mITT) population was 1291 patients (pts); 641 in the 6-month arm (6 mo) and 650 in the 3-month arm (3 mo). Baseline population were well balanced across the 2 treatment groups. Median (Min-Max) of Age, were 66 (28-85) in 6-month arm and 66 (29-85) in 3-month arm. The proportions of > 70 years old were 34.5% and 34.5%, Received XELOX 75.2% and 74.9%, Female 50.1% and 49.4%, ECOG PS=1 3.0% and 4.2%, T stage=T4 27.8% and 28.5%, N stage=N2 25.9% and 25.5%, High risk group (T4 or N2) 44.9% and 43.8%, Sideness=Right colon 39.6% and 36.8%.

Participant flow

1.Registration period and Site
The target number of 1200 pts was planned to be accumulated in the registration period of 3 years, but 1313 pts were registered in about 2 years from the start of registration. A total of 249 pts was registered at 10 sites with more than 20 pts registered, accounting for about 1/5 of the total. There were no patient registrations at 75 of the 318 sites.

2.Patient disposition
Registration 1313 pts (656 in 6-month arm, 657 in 3-month arm)
Not treated 22 pts (15 in 6-month arm, 7 in 3-month arm)
mITT 1291 pts (641 in 6-month arm, 650 in 3- month arm)
Protocol treatment discontinued 329 pts (236 in 6-month arm, 93 in 3-month arm)
Protocol treatment completed 962 pts (405 in 6-month arm, 557 in 3-month arm)

Adverse events

1.Adverse events of mFOLFOX6 during treatment In grade 3 or higher adverse events, "Neutropenia" was most frequent with 34.6% in 6-month arm and 26.4% in 3-month arm, secondly "Leukopenia" 5.7% and 7.4%. "Peripheral Sensory Neuropathy (PSN)r" was more frequently observed in 6-month arm with 5.0% than in 3-month arm with 0.6%.

2.Adverse events of XELOX during treatment
In grade 3 or higher adverse events, "Neutropenia" was most frequent with 15.4% in 6-month arm and 9.4% in 3-month arm, secondly "thrombocytopenia", "diarrhea" and "anorexia," with 5.6%, 5.4%, and 5.4% in 6-month arm and 3.5%, 5.5%, and 4.9% in 3-month arm. PSN was more frequently observed in 6-month arm with 6.2% than in 3-month arm with 1.0%.

3.Comparison between treatment groups and regimen Adverse events of grade 3 or higher tended to be more frequent in 6-month arm than in 3-month arm. Particularly, there was a large difference between both arms in PSN. In addition, "neutropenia" was less frequently observed with XELOX.

4.Time course of PSN The incidence of grade 1-3 during the treatment period was 89.3%, 79.7%, 74.8%, and 72.3% mFOLFOX6 in 6-month arm, XELOX in 6-month arm, mFOLFOX6 in 3-month arm, XELOX in 3-month arm, respectively. There was a tendency to be less for XELOX than mFOLFOX6 and 3-month arm than 6-month arm. The incidence of grade 1-3 decreased year by year to 36.8%, 26.1%, 14.8%, 10.1% after 3 years, and 21.3%, 14.8%, 8.5%, 7.3% after 6 years.

Outcome measures

Disease-free survival*1
*1: DFS is defined as relapse or death by IDEA.

(1) Disease-free survival*2
*2: DFS is defined as relapse, second cancer or death.
(2) Time to treatment failure
(3) Overall survival
(4) Adverse events
(5) Completion rate
(6) Relative dose intensity
(7) Peripheral neuropathy
(8) Lymph node metastasis, lymph node dissection, lymph nodes examined, and prognosis
(9) Exploration of prognostic indicators and adverse events
(Additional study: Pharmacogenomics).

Plan to share IPD

IPD sharing Plan description

Recruitment status

Completed

Date of protocol fixation

2012

Year

04

Month

19

Day

Date of IRB

2018

Year

12

Month

27

Day

Anticipated trial start date

2012

Year

08

Month

01

Day

Last follow-up date

2020

Year

06

Month

30

Day

Date of closure to data entry

Date trial data considered complete

Date analysis concluded

Other related information

Registered date

2012

Year

07

Month

26

Day

Last modified on

2022

Year

06

Month

22

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000010043