UMIN-CTR Clinical Trial

Public title

Expiratory randomized phase II trial for optimizing treatment dose and duration of adjuvant S-1 plus oxaliplatin in patients with stage III colon cancer

Acronym

Expiratory randomized phase II trial for optimizing treatment dose and duration of adjuvant S-1 plus oxaliplatin in patients with stage III colon cancer(SOAP trial)

Scientific Title

Expiratory randomized phase II trial for optimizing treatment dose and duration of adjuvant S-1 plus oxaliplatin in patients with stage III colon cancer

Scientific Title:Acronym

Expiratory randomized phase II trial for optimizing treatment dose and duration of adjuvant S-1 plus oxaliplatin in patients with stage III colon cancer(SOAP trial)

Region

Japan

Condition

colon cancer

Classification by specialty

Gastrointestinal surgery

Classification by malignancy

Malignancy

Genomic information

NO

Narrative objectives1

The subject of this randomised phase II trial is to determine optimal dose and treatment dulation of adjuvant S-1 plus oxaliplatin in patients with stage III colon cancer

Basic objectives2

Safety,Efficacy

Basic objectives -Others

Trial characteristics_1

Exploratory

Trial characteristics_2

Pragmatic

Developmental phase

Phase II

Primary outcomes

Disease free survival

Key secondary outcomes

1)Relative Dose Intensity
2)completion rate
3)Relapse free survival
4)Overall survival
5)time-dependent change of peripheral neuropathy
6)Adverse event rate

Study type

Interventional

Basic design

Parallel

Randomization

Randomized

Randomization unit

Individual

Blinding

Open -no one is blinded

Control

Dose comparison

Stratification

NO

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

arm A: L-OHP 100mg/m2, 8 courses (24 weeks)
1) 2 hour bolus infusion of 100mg/m2 of L-OHP on day1
2)According to BSA, from 80mg to 120mg of S-1 is taken divided twice a day from day 1 to day 15.
3) Period of one course is 21 days, 8 courses(24 weeks) is performed.

Interventions/Control_2

arm B: L-OHP 130mg/m2, 4 courses (12 weeks)
1) 2 hour bolus infusion of 130mg/m2 of L-OHP on day1
2)According to BSA, from 80mg to 120mg of S-1 is taken divided twice a day from day 1 to day 15.
3) Period of one course is 21 days, 4 courses(12 weeks) is performed

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

80

years-old

>=

Gender

Male and Female

Key inclusion criteria

1) clinical stage II, III
2) tumor location is from cecum to rectosigmoid.
3) aged between 20 and 80 years old
4) ECOG Performance status of 0 or 1
5) no prior chemotherapy or radiotherapy
6) oral intake is possible
7) adequate bone marrow function with absolute neutrophil count >=1,500/microl, platelet count >=100,000/microl, adequate liver function with total bilirubin =<2 x upper limit of normal (ULN), aspartate aminotransferase (AST), alanine aminotransferase (ALT) =<100IU/L, adequate renal function with Ccr >= 60ml/min
8) Able to start protocol treatment within 8 weeks of surgical procedure.
8) willing to provide written informed consent.

Key exclusion criteria

1) Tumor located below the peritoneum.
2) history of another malignancy within 5 years
3) Severe postoperattive complication (such as severe infection, severe anastomoitc leakage, intestinal bleeding)
4) Severe concurrent disease such as poorly controlled hypertension, poorly controlled diabetes, interstitial pneumonia or pulmonary fibrosis, severe chronic pulmonary emphysema, heart failure, renal failure, hepatic failure.
5) Severe sensory disorder
6) Severe diarrhea
7) history of severe drug hypersensitivity
8) administration of flucytosine
9) Pregnant females, possibly pregnant females, females wishing to become pregnant and nursing mothers. Males who are currently attempting to produce a pregnancy
10) Severe psychiatric disorder
11) Physician concludes that the patient's participation in this trial is inappropriate.

Target sample size

160

Name of lead principal investigator

1st name	Jun
Middle name
Last name	Watanabe

Organization

Yokohama City University Medical Center

Division name

Gastroenerological Center

Zip code

232-0024

Address

4-57 Urafune-cho, Minami-ku, Yokohama City, 232-0024, Japan

TEL

045-261-5656

Email

nabe-jun@comet.ocn.ne.jp

Name of contact person

1st name	Jun
Middle name
Last name	Watanabe

Organization

Yokohama City University Medical Center

Division name

Gastroenerological Center

Zip code

232-0024

Address

4-57 Urafune-cho, Minami-ku, Yokohama City, 232-0024, Japan

TEL

045-261-5656

Homepage URL

Email

nabe-jun@comet.ocn.ne.jp

Institute

Yokohama City University Medical Center

Institute

Department

Personal name

Organization

TAIHO PHARMACEUTICAL CO.

Organization

Division

Category of Funding Organization

Profit organization

Nationality of Funding Organization

JAPAN

Co-sponsor

Name of secondary funder(s)

Organization

Yokohama City University Ethics Committee

Address

3-9 Fukuura, Kanazawa-ku, Yokohama City, 236-0004, Japan

Tel

045-370-7629

Email

nextjim1@yokohama-cu.ac.jp

Secondary IDs

NO

Study ID_1

Org. issuing International ID_1

Study ID_2

Org. issuing International ID_2

IND to MHLW

Institutions

横浜市立大学附属市民総合医療センター（神奈川県）
横浜市立大学附属病院（神奈川県）
横須賀共済病院（神奈川県）
横浜市立市民病院（神奈川県）
藤沢市民病院（神奈川県）
済生会横浜市南部病院（神奈川県）
独立行政法人国立病院機構横浜医療センター（神奈川県）
横浜みなと赤十字病院（神奈川県）
横浜保土ヶ谷中央病院（神奈川県）
横須賀市立市民病院（神奈川県）
伊東市民病院（神奈川県）
NTT東日本関東病院（神奈川県）
済生会若草病院（神奈川県）
横浜掖済会病院（神奈川県）
長津田厚生総合病院（神奈川県）

Date of disclosure of the study information

2014

Year

04

Month

28

Day

URL releasing protocol

None

Publication of results

Published

URL related to results and publications

None

Number of participants that the trial has enrolled

163

Results

The 3 year DFS was not significantly superior to null hypothesis in both 3 months and 6 months arms for the patients of stage III colon cancer. Primary endpoint was not achieved. The SOX regimen was not feasible in long term outcomes.

Results date posted

2024

Year

11

Month

13

Day

Results Delayed

Results Delay Reason

Date of the first journal publication of results

Baseline Characteristics

The median age of all eligible patients was 64.5 (58.0-69.5) years in group A (6-month group) and 65.0 (57.0-70.0) years in group B (3-month group),
In group A, 73 (96.1%) had PS 0 and 3 (3.9%) had PS 1; in group B, 77 (97.5%) had PS 0 and 2 (2.5%) had PS 1; in group A, 49 (64.5%) were male and 27 (35.5%) were female; in group B, 42 (53.2%) were male and 37 (46.8%) were female. There was no significant difference between the two groups.
In terms of histopathological findings of the primary tumor, wall depth T3/T4 was 58 (76.3%) in group A and 62 (78.5%) in group B. Lymph node metastasis pN2a/pN2b was 15 (19.8%) in group A and 18 (22.8%) in group B. The proportion of high-risk stage III patients was similar between the two groups.

Participant flow

Between April 30, 2014 and November 17, 2017, a total of 163 enrolled patients from nine Yokohama Clinical Oncology Group (YCOG) medical centers were randomly assigned to either group A or group B of SOX-assisted chemotherapy. 82 patients in group A and 81 patients in group B were assigned, with one patient in each group found ineligible after enrollment One patient in each group was found to be ineligible after enrollment, as well as one patient in group A who received the wrong dose of LOHP due to an allocation group error, four patients in group A and one patient in group B who did not start treatment because they did not meet the initiation criteria were excluded from all eligible cases. The final analysis was performed on all eligible patients (76 in Group A and 79 in Group B).
Fifty-six patients in Group A (73.7%) and 68 patients in Group B (86.1%) completed postoperative SOX therapy as specified in the protocol. Most of the reasons for discontinuation of postoperative SOX therapy were that treatment could not be resumed or started after the last dose of S1 (3 patients in Group A and 5 patients in Group B) or that the subject requested discontinuation of protocol treatment (10 patients in Group A and 2 patients in Group B).

Adverse events

Serious adverse events were observed in one patient in group A (hypophosphatemia Grade 4, neutropenia Grade 4, hypokalemia Grade 3, and anorexia Grade 4) (causal relationship, outcome recovered). Grade 3 or higher adverse events that occurred in more than 10% of patients in either group were anorexia (10.5% in group A and 3.8% in group B), diarrhea (11.8% in group A and 13.9% in group B), and neutropenia (19.7% in group A and 13.9% in group B).

Outcome measures

1. Primary Endpoint
The primary endpoint of this study was disease free survival (DFS) to determine whether the 3-year DFS rate of protocol treatment was effective enough to reject the threshold (P0) in each group. The threshold was set at P0=72%, and the significance level for the test was 10% one-sided.
The 3-year DFS rates were 75.0% (80% CI 67.9580.72, p=0.2822) for group A and 76.9% (80% CI 70.1-82.38, p=0.1708) for group B. Both groups were not significantly above the DFS threshold (P0) for protocol treatment.

Secondary endpoints
1) Overall survival OS
1-year OS was 100% (95% CI NA-NA) in Group A and 98.72% (95% CI 91.25-99.82) in Group B. 2-year OS was 100% (95% CI NA-NA) in Group A and 98.72% (95% CI 91.25-99.82) in Group B. 3-year OS was 97.3% (95 CI 89.62-99.32) in group A, 97.44% (95% CI 90.13-99.35) in group B, 94.56% (95% CI 86.14-97.92) in group A, 96.15% (95% CI 88.55-98.74) in group B, and 93.19% (95% CI 84.4-97.74) in group A. The 4-year OS was 94.56% (95% CI 86.14-97.92) in group A, 96.15% (95% CI 88.55-98.74) in group B, and 5-year OS was 93.19% (95% CI 84.4-97.11) and 96.15% (95% CI 88.55-98.74) in group B.

2) Relapse-free survival (RFS)
1-year RFS was 92.11% (95%CI 83.27-96.37) in group A and 93.59% (95%CI 85.28-97.28) in group B. 2-year RFS was 85.53% (95%CI 75.39-91.71) in group A and 82.05% (95%CI 71.58-88.95) in group B, 3-year RFS was 82.89% (95%CI 72.37-89.69) in group A and 78.21% (95%CI 67.31-85.84) in group B. 4-year RFS was 82.89% (95%CI 72.37-89.69) in group A and 76.92% (95%CI 65.90-84.78) in group B, 5-year RFS was 82.89% (95%CI 72.37-89.69) in group A and 75.64% (95%CI 64.51-83.71) in group B.

3) Disease-free survival (DFS)
1-year DFS was 92.11% (95%CI 83.27-96.37) in group A and 92.31% (95%CI 83.68-96.47) in group B. 2-year DFS was 78.95% (95%CI 67.9686.53) in group A and 80.77% (95%CI 70.14-87.93) in group B. 3-year DFS was 92.11% (95%CI 83.27-96.37) in group B and 92.31% (95%CI 83.68-96.47) in group A. DFS at 3 years was 75.0% (95%CI 63.65-83.26) in group A and 76.92% (95%CI 65.9-84.78) in group B, 4-year DFS was 73.66% (95%CI 62.21-82.13) in group A and 74.36% (95%CI 63.13-82.63) in group B, and 5-year DFS was 73.66% (95%CI 62.21-82.13) in group A and 71.79% (95%CI 60.4-80.43) in group B.

4) Relative Dose Intensity (RDI)
The mean RDI of S-1 was 76.9% in group A and 82.6% in group B (p=0.030). The mean RDI of oxaliplatin was 77.4% in group A and 85.0% in group B (p=0.002).

5) Percentage of treatment completion
Treatment completion rate was 73.7% in group A and 86.1% in group B (p=0.070).

6) Changes over time in peripheral neuropathy (PNQ)
No differences in sensory and motor peripheral neuropathy were found between the two groups in pre- and post-treatment changes in PNQ scores. However, the collection rate of PNQ score data was low in both PNQ groups, which was insufficient to accurately assess the extent of peripheral neuropathy.

Plan to share IPD

IPD sharing Plan description

Recruitment status

Completed

Date of protocol fixation

2014

Year

03

Month

06

Day

Date of IRB

2014

Year

04

Month

17

Day

Anticipated trial start date

2014

Year

04

Month

28

Day

Last follow-up date

2022

Year

12

Month

31

Day

Date of closure to data entry

Date trial data considered complete

Date analysis concluded

Other related information

Registered date

2014

Year

04

Month

28

Day

Last modified on

2024

Year

11

Month

13

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000016135