UMIN-ICDS Clinical Trial

Public title

A Randomized Phase III Study Comparing Pathology Artificial Intelligence (AI)- and Circulating Tumor DNA (ctDNA)-Guided Adjuvant Chemotherapy with Standard Adjuvant Therapy for Patients with Curatively Resected High-Risk Stage II and Stage III Colon Cancer

Acronym

LIBRA-Japan trial

Scientific Title

A Randomized Phase III Study Comparing Pathology Artificial Intelligence (AI)- and Circulating Tumor DNA (ctDNA)-Guided Adjuvant Chemotherapy with Standard Adjuvant Therapy for Patients with Curatively Resected High-Risk Stage II and Stage III Colon Cancer

Scientific Title:Acronym

LIBRA-Japan trial

Region

Japan

Condition

Patients with Curatively Resected High-Risk Stage II and Stage III Colon Cancer

Classification by specialty

Gastrointestinal surgery

Classification by malignancy

Malignancy

Genomic information

YES

Narrative objectives1

This study aims to evaluate, in a prospective randomized international project, whether a postoperative adjuvant chemotherapy strategy based on recurrence risk assessment using CAPAI (Combined Analysis of Pathologists and Artificial Intelligence) with DoMore-v1-CE-CRC and molecular residual disease (MRD) detection by circulating tumor DNA (ctDNA) is non-inferior to standard postoperative adjuvant chemotherapy in terms of disease-free survival (DFS) among patients with high-risk stage II and stage III colon cancer who have undergone curative resection (experimental treatment group: Arm A vs. control group: Arm B).

The project will validate this hypothesis through an integrated analysis of data from randomized phase III trials conducted in Japan, the United Kingdom, and Norway. Data collected in Japan will be transferred to the Institute for Cancer Genetics and Informatics (ICGI) at Oslo University, where the pooled analyses will be performed jointly by ICGI and the University of Oxford.

If non-inferiority of the adjuvant chemotherapy strategy guided by CAPAI and MRD-based recurrence risk assessment is demonstrated, it may be possible to reduce the use of adjuvant chemotherapy while maintaining its efficacy in preventing cancer recurrence. Consequently, the number of patients requiring postoperative adjuvant chemotherapy could be decreased, potentially reducing the risk of treatment-related adverse effects and improving patient quality of life.

Basic objectives2

Safety,Efficacy

Basic objectives -Others

Trial characteristics_1

Confirmatory

Trial characteristics_2

Pragmatic

Developmental phase

Phase III

Primary outcomes

To evaluate whether there is a difference in disease-free survival (DFS) between a biomarker-guided treatment strategy based on CAPAI and ctDNA results and the standard treatment strategy in patients with high-risk Stage II and Stage III colon cancer who have undergone curative resection.

Key secondary outcomes

(1) Time to Recurrence (TTR)
(2) Cancer-Specific Survival (CSS)
(3) Overall Survival (OS)
(4) Safety Outcomes
(5) Improvement in Quality of Life (QOL), as Reported by Patients
(6) Concordance Rate Between AI-Based Pathological Assessments Performed on the Largest Tumor Section in the Central Review and AI-Based Pathological Assessments Performed on Specimens Submitted for MONSTAR-3.5 MUGEN
(7) Analysis of the Prognostic Value of CAPAI and ctDNA Individually

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 not considered as adjustment factor.

Blocking

NO

Concealment

No. of arms

2

Purpose of intervention

Diagnosis

Type of intervention

Other

Interventions/Control_1

Arm A (Biomarker-Guided Arm)
In Arm A, postoperative recurrence risk is assessed using both CAPAI (Combined Analysis of Pathologists and Artificial Intelligence) and circulating tumor DNA (ctDNA) testing. Patients classified as high-risk or intermediate-risk by CAPAI, or those with a positive ctDNA result, are considered to be at high risk of recurrence and will receive adjuvant chemotherapy at the discretion of the treating physician. In contrast, patients classified as low-risk by CAPAI and negative for ctDNA are considered to be at low risk of recurrence and will undergo observation without adjuvant chemotherapy. All patients will be followed for five years and will undergo ctDNA surveillance. ctDNA surveillance will be performed every three months during the first year and every six months during the second year.

Interventions/Control_2

Arm B (Standard Treatment Arm)
In Arm B, CAPAI and ctDNA testing will be performed; however, the results will not be disclosed to the treating physician. Therefore, decisions regarding the indication for adjuvant chemotherapy and the treatment regimen will be made by the treating physician according to standard clinical practice, based on conventional clinical and pathological factors such as disease stage and pathological findings. Adjuvant chemotherapy, when indicated, will be initiated within six weeks after surgery. As in Arm A, all patients will be followed for five years and will undergo ctDNA surveillance.

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

18

years-old

<=

Age-upper limit

Not applicable

Gender

Male and Female

Key inclusion criteria

Patients who meet all of the following inclusion criteria and none of the exclusion criteria will be eligible for enrollment in this study.
(1) Histologically confirmed colonic adenocarcinoma, including tumors arising in the rectosigmoid colon as defined by the Japanese Classification of Colorectal, Appendiceal, and Anal Carcinoma, 9th Edition.
(2) Aged 18 years or older at the time of informed consent.
(3) Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1.
(4) Have undergone curative (R0) resection with D2 or D3 lymph node dissection.
(5) Have high-risk Stage II disease (defined by the presence of at least one of the recurrence risk factors (a)-(e) below) or Stage III disease:
(a) T4 disease (SE/SI/AI)
(b) Fewer than 12 lymph nodes examined
(c) Clinically diagnosed bowel obstruction, perforation, or penetration
(d) Poorly differentiated adenocarcinoma, signet-ring cell carcinoma, or mucinous adenocarcinoma
(e) Vascular, lymphatic, or perineural invasion
(6) No radiological evidence of metastatic disease within 90 days prior to registration.
(7) Availability of a surgically resected primary colon tumor specimen.
(8) Adequate organ function within 35 days prior to registration.
(9) Registration conducted 2 to 6 weeks after curative resection.
(10) Enrollment in the MONSTAR-3.5 MUGEN Study.
(11) Provision of written informed consent by the patient for participation in this study.

Key exclusion criteria

(1) Two or more synchronous primary colon cancers.
(2) History of prior malignancy.
Eligible if recurrence-free for more than 5 years or if the malignancy was cured by local treatment, e.g. basal or squamous cell skin cancer, superficial bladder cancer, cervical cancer, carcinoma in situ, intramucosal carcinoma, or non-metastatic prostate cancer not requiring systemic therapy.
(3) Known MSI-H or MMR deficiency.
(4) Chemotherapy, immunotherapy, or radiotherapy within 6 months before registration.
(5) Pregnant or breastfeeding women.
(6) Unwillingness to use contraception during treatment and for 30 days thereafter.
(7) History of bone marrow or solid organ transplantation.
(8) Uncontrolled heart failure, angina, hypertension, arrhythmia, or diabetes.
(9) Uncontrolled active seizure disorder.
(10) Active or chronic infection requiring systemic therapy.
(11) Grade 2 or higher sensory or motor neuropathy (CTCAE v5.0).
(12) Positive HBsAg or HCV antibody.
(13) Positive HIV antibody (Patients may be enrolled even if HIV antibody testing has not been performed).
(14) Known DPD deficiency.
(15) History of hypersensitivity to oxaliplatin, LV, 5-FU, or capecitabine.
(16) Any condition deemed unsuitable by the Principal Investigator.

Target sample size

1053

Name of lead principal investigator

1st name	Takayuki
Middle name
Last name	Yoshino

Organization

National Cancer Center Hospital East

Division name

Department of International Clinical Development

Zip code

277-8577

Address

6-5-1 Kashiwanoha, Kashiwa-shi Chiba, Japan

TEL

04-7133-1111

Email

tyoshino@east.ncc.go.jp

Name of contact person

1st name	Tadayoshi
Middle name
Last name	Hashimoto

Organization

National Cancer Center Hospital East

Division name

Department of Gastrointestinal Medical Oncology

Zip code

277-8577

Address

6-5-1 Kashiwanoha, Kashiwa-shi Chiba, Japan

TEL

04-7133-1111

Homepage URL

Email

tadhashi@east.ncc.go.jp

Institute

National Cancer Center Hospital East

Institute

Department

Personal name

Organization

Myriad Genetics,lnc/National Cancer Center Hospital East

Organization

Division

Category of Funding Organization

Other

Nationality of Funding Organization

Japan

Co-sponsor

iTMS,lnc/Oslo University/University of Oxford

Name of secondary funder(s)

Organization

National Cancer Center Institutional Review Board

Address

5-1-1 Tsukiji, Chuo-ku, Tokyo, Japan

Tel

03-3542-2511

Email

NCC_IRBoffice@ml.res.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

国立がん研究センター東病院、北海道大学病院、手稲渓仁会病院、弘前大学医学部附属病院、東北大学病院、仙台市医療センター 仙台オープン病院、総合病院土浦協同病院、埼玉県立がんセンター、地方独立行政法人東京都立病院機構 東京都立駒込病院、東邦大学医療センター佐倉病院、帝京大学ちば総合医療センター、千葉大学大学院医学研究院、北里大学医学部、神奈川県立がんセンター、横浜市立大学附属市民総合医療センター、聖マリアンナ医科大学病院、静岡県立静岡がんセンター、新潟大学医歯学総合病院、岐阜大学医学部附属病院、岐阜市民病院、岐阜県総合医療センター、大阪医科薬科大学、関西医科大学附属病院、大阪大学医学部附属病院、市立豊中病院、大阪医療センター、大阪国際がんセンター、大阪国際メディカル＆サイエンスセンター 大阪けいさつ病院、市立東大阪医療センター、大阪急性期・総合医療センター、近畿大学医学部、大阪ろうさい病院、関西労災病院、兵庫医科大学病院、姫路赤十字病院、医療法人薫風会佐野病院、りんくう総合医療センター、公益財団法人大原記念倉敷中央医療機構 倉敷中央病院、広島大学大学院 医系科学研究科、島根県立中央病院、産業医科大学病院、九州大学病院、国立病院機構九州医療センター、独立行政法人国立病院機構九州がんセンター、済生会福岡総合病院、熊本大学病院、市立池田病院

Date of disclosure of the study information

2026

Year

09

Month

02

Day

URL releasing protocol

Publication of results

Unpublished

URL related to results and publications

Number of participants that the trial has enrolled

Results

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

Preinitiation

Date of protocol fixation

2026

Year

08

Month

26

Day

Date of IRB

2026

Year

09

Month

01

Day

Anticipated trial start date

2026

Year

09

Month

15

Day

Last follow-up date

2034

Year

03

Month

31

Day

Date of closure to data entry

Date trial data considered complete

Date analysis concluded

Other related information

This study will be conducted using secondary use of CAPAI and circulating tumor DNA (ctDNA) analysis results derived from biospecimens and clinical data collected in the preceding MONSTAR-3.5 MUGEN study (UMIN000060793). The MONSTAR-3.5 MUGEN study serves as a foundational research project that generates biomarker information based on CAPAI and ctDNA. The LIBRA trial is an international Phase III study designed to evaluate whether the use of these biomarkers to guide treatment decision-making can reduce the use of adjuvant chemotherapy while maintaining clinical outcomes following curative resection.

Registered date

2026

Year

09

Month

02

Day

Last modified on

2026

Year

09

Month

02

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000071397