UMIN-CTR Clinical Trial

Basic information
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
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

Objectives
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

Assessment
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).

Base
Study type	Interventional

Study design
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

Intervention
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

Eligibility
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

Research contact person
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

Public contact
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

Sponsor
Institute	Japanese Foundation for Multidisciplinary Treatment of Cancer
Institute
Department

Funding Source
Organization	Yakult Honsha Co., Ltd.
Organization
Division
Category of Funding Organization	Profit organization
Nationality of Funding Organization

Other related organizations
Co-sponsor
Name of secondary funder(s)

IRB Contact (For public release)
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
Secondary IDs	NO
Study ID_1
Org. issuing International ID_1
Study ID_2
Org. issuing International ID_2
IND to MHLW

Institutions
Institutions

Other administrative information
Date of disclosure of the study information	2012 Year 08 Month 01 Day

Related information
URL releasing protocol	https://www.jfmc.or.jp/ex/wp-content/uploads/2015/01/jfmc47_1202_c3.pdf
Publication of results	Published

Result
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

Progress
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
Other related information

Management information
Registered date	2012 Year 07 Month 26 Day
Last modified on	2022 Year 06 Month 22 Day

Link to view the page
URL(English)	https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000010043