UMIN-CTR Clinical Trial
| Unique ID issued by UMIN | UMIN000036690 |
|---|---|
| Receipt number | R000041811 |
| Scientific Title | C" Study |
| Date of disclosure of the study information | 2019/05/10 |
| Last modified on | 2026/09/02 17:50:44 |
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Basic information
Public title
An observational study to follow clinical outcomes for the patients participated in the randomized, phase III trial of sequential capecitabine/5FU plus bevacizumab (Cape/5FU-Bmab) to capecitabine/5FU plus oxaliplatin plus bevacizumab (CapeOX/mFOLOFX6-Bmab) versus combination CapeOX/mFOLFOX6-Bmab in advanced colorectal cancer
Acronym
C" Study
Scientific Title
C" Study
Scientific Title:Acronym
C" Study
Region
| Japan |
Condition
Condition
Colorectal Cancer
Classification by specialty
| Gastroenterology | Hepato-biliary-pancreatic medicine | Hematology and clinical oncology |
| Gastrointestinal surgery |
Classification by malignancy
Malignancy
Genomic information
NO
Objectives
Narrative objectives1
Follow the prognosis of C-cubed study participants.
Collect RAS and BRAF gene mutation spectrum information.
Basic objectives2
Others
Basic objectives -Others
Among the participating patients in C-cubed Study, we are planing to collect tumor tissues and analyze cancer-related genetic, epigenetic and immunological alterations by using DNA, RNA and IHC.
Trial characteristics_1
Trial characteristics_2
Developmental phase
Assessment
Primary outcomes
Final update of OS in C-cubed study.
Determination of patient population to RAS/BRAF mutations.
Key secondary outcomes
Among the participating patients in C-cubed Study, we are planing to collect tumor tissues and analyze cancer-related genetic, epigenetic and immunological altelations by using DNA/RNA and IHC.
Base
Study type
Observational
Study design
Basic design
Randomization
Randomization unit
Blinding
Control
Stratification
Dynamic allocation
Institution consideration
Blocking
Concealment
Intervention
No. of arms
Purpose of intervention
Type of intervention
Interventions/Control_1
Interventions/Control_2
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
| Not applicable |
Age-upper limit
| Not applicable |
Gender
Male and Female
Key inclusion criteria
patients wwho paticipated in the C- cubed study/
Key exclusion criteria
none
Target sample size
311
Research contact person
Name of lead principal investigator
| 1st name | Yoshiyuki Yamaguchi |
| Middle name | |
| Last name | Masasumi Okajima |
Organization
Kawasaki medical school/JSWOG
Division name
Department of Clinical Oncology
Zip code
701-0192
Address
577 Matsushima, Kurashiki
TEL
0864621111
shogo@med.kawasaki-m.ac.jp
Public contact
Name of contact person
| 1st name | Takeshi |
| Middle name | |
| Last name | Nagasaka |
Organization
Kawasaki Medical School
Division name
Department of Clinical Oncology
Zip code
701-0192
Address
577 Matsushima, Kurashiki
TEL
0864621111
Homepage URL
takeshin@med.kawasaki-m.ac.jp
Sponsor or person
Institute
Department of Clinical Oncology, Kawasaki MEdical School
JSWOG
Institute
Department
Personal name
Funding Source
Organization
Kawasaki Medical School
Organization
Division
Category of Funding Organization
Self funding
Nationality of Funding Organization
Japan
Other related organizations
Co-sponsor
Name of secondary funder(s)
IRB Contact (For public release)
Organization
Kawasaki Medical School
Address
577 Matsushima, Kurashiki
Tel
086-462-1111
rinri@hp.kawasaki-m.ac.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
| 2019 | Year | 05 | Month | 10 | Day |
Related information
URL releasing protocol
https://www.nature.com/articles/s43856-026-01633-3
Publication of results
Published
Result
URL related to results and publications
https://www.nature.com/articles/s43856-026-01633-3
Number of participants that the trial has enrolled
300
Results
Median overall survival is 27.2 months with sequential treatment and 27.4 months with upfront treatment (hazard ratio, 1.00; 95% confidence interval, 0.76-1.33; p = 0.98). Additional time-restricted and milestone analyses show no between-group differences. There is no evidence that age modifies the relative treatment effect. Patient-reported outcomes indicate a lower early treatment burden with sequential treatment, including smaller early declines in physical functioning and less sensory neuropathy.
Results date posted
| 2026 | Year | 09 | Month | 02 | Day |
Results Delayed
Results Delay Reason
Date of the first journal publication of results
| 2026 | Year | 05 | Month | 08 | Day |
Baseline Characteristics
This open-label, randomized, multicenter phase III trial evaluated two treatment strategies for metastatic colorectal cancer (mCRC). A total of 311 patients were randomized 1:1 into Arm A (sequential treatment: FP plus BEV with escalation to OX upon progression) or Arm B (upfront combination therapy: OX, FP, and BEV); the full analysis set comprised 300 patients. Patients were allocated across 81 Japanese institutions, with stratification by critical variables including study site, Kohne Index (low/intermediate/high), and prior adjuvant chemotherapy (with or without OX)15,16. The primary endpoint, time to failure strategy (TFS), was previously reported14. Patients were accrued in the original C-cubed trial between December 2014 and September 2016 across 81 participating institutions in Japan. This update focuses on overall survival, with follow-up completed by the data cutoff date (31 July 2020).
Participant flow
Baseline demographic and clinical data were collected, including age, sex, Eastern Cooperative Oncology Group (ECOG) performance status (PS), tumor characteristics, laboratory parameters, and prior treatments. Patients were categorized by age into <70 years and >70 years.
Adverse events
Among treated patients with evaluable safety data, all-grade sensory neuropathy was more frequent with upfront OX exposure in both age strata, occurring in 80.6 versus 64.6% of patients aged <70 years and in 78.9 versus 38.9% of those aged >70 years (Arm B versus Arm A), whereas grade >3 sensory neuropathy remained uncommon (5.6 and 6.6% in Arm B among patients aged <70 and >70 years, respectively, versus 0% in both strata in Arm A). All-grade hematologic toxicities, particularly neutropenia, lymphopenia, and thrombocytopenia, were also numerically more frequent with upfront therapy, whereas hand-foot syndrome was more frequent with sequential treatment. This pattern was consistent with the patient-reported neuropathy findings shown in Fig. 3C. Detailed adverse-event data were provided in Supplementary Data 4.
Outcome measures
Updated OS
Median follow-up was 42.7 months (IQR, 33.1-52.4) as determined by the reverse Kaplan-Meier method at the data cutoff date (31 July 2020). In the FAS, median OS was 27.2 months in Arm A (95% CI [24.4-33.3 months]) and 27.4 months in Arm B (95% CI [23.2-36.8 months]). No statistically significant difference was detected between strategies (HR [B vs. A] = 1.00, 95% CI [0.76-1.33] Wald p = 0.98). Kaplan-Meier curves suggested early separation in favor of Arm A (Fig. 2A), prompting prespecified PH checks and complementary RMST/milestone analyses. The PH test did not indicate a violation overall (slope = -0.056; p = 0.22).
Age-stratified Analyses
Age-stratified analyses showed no significant age x treatment interaction for OS (interaction p = 0.45). Within each treatment arm, older patients (>= 70 years) had shorter OS compared with younger patients (< 70 years), with HRs of 1.44 (95% CI, 0.96-2.16) in the sequential arm and 1.77 (95% CI, 1.17-2.66) in the upfront combination arm (Fig. 2B). These findings indicate that age itself was associated with prognosis, but did not significantly modify the relative treatment effect between strategies.
Tumor Location and RAS/BRAF Mutation Status
Tumor biology strongly influenced survival outcomes across treatment arms. Patients with left-sided primary tumors consistently demonstrated longer OS than those with right-sided tumors (Supplementary Fig. S1). Similarly, OS differed markedly by RAS/BRAF mutation status, following a consistent gradient of wild-type > RAS-mutant > BRAF V600E-mutant disease (Supplementary Fig. S2). These patterns were observed irrespective of treatment strategy, underscoring the dominant prognostic role of tumor location and molecular subtype.
RMST and Milestone Analyses
RMST and milestone OS analyses across prespecified time horizons (24 and 36 months) yielded results concordant with the primary OS analysis, with only small, non-significant differences between strategies across age groups, tumor location, and RAS/BRAF status (Supplementary Tables S1A-S1D and S2A-S2D).
QoL (pre-planned secondary endpoints)
A total of 292 patients were enrolled in the QoL substudy (Arm A, n = 148; Arm B, n = 144). Across prespecified instruments, longitudinal patterns were broadly consistent with a lower early treatment burden with the sequential strategy. In the EORTC QLQ-C30, sequential therapy showed smaller early declines in physical (and role) functioning at 6 and 12 months, with attenuation by 18 months; changes in cognitive functioning and fatigue numerically favored Arm A but were modest and not statistically different between arms (Fig. 3A; Supplementary Data 2). EQ-5D-3L analyses showed a larger decline in health utility at 6 months with upfront therapy, followed by partial convergence at later time points (Fig. 3B; Supplementary Data 2). Peripheral neuropathy assessed by the PNQ increased more with upfront OX exposure at 6 and 12 months, particularly in the sensory domain, while motor symptoms remained mild; between-arm differences narrowed by 18 months (Fig. 3C; Supplementary Data 2). All QoL comparisons were exploratory and unadjusted for multiplicity.
Plan to share IPD
None
IPD sharing Plan description
None
Progress
Recruitment status
Main results already published
Date of protocol fixation
| 2019 | Year | 05 | Month | 01 | Day |
Date of IRB
| 2019 | Year | 07 | Month | 17 | Day |
Anticipated trial start date
| 2019 | Year | 06 | Month | 10 | Day |
Last follow-up date
| 2022 | Year | 03 | Month | 31 | Day |
Date of closure to data entry
| 2022 | Year | 09 | Month | 30 | Day |
Date trial data considered complete
| 2023 | Year | 03 | Month | 31 | Day |
Date analysis concluded
| 2023 | Year | 03 | Month | 31 | Day |
Other
Other related information
None
Management information
Registered date
| 2019 | Year | 05 | Month | 09 | 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=R000041811
