Colorectal Cancer
Conditions
Keywords
adenocarcinoma of the colon, stage III colon cancer
Brief summary
PURPOSE: This randomized phase III trial is studying giving oxaliplatin, leucovorin calcium, and fluorouracil together to compare how well they work when given together with or without celecoxib in treating patients with stage III colon cancer previously treated with surgery. RATIONALE: Drugs used in chemotherapy, such as oxaliplatin, leucovorin calcium, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Celecoxib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether giving oxaliplatin, leucovorin calcium, and fluorouracil is more effective with or without celecoxib in treating colon cancer.
Detailed description
OUTLINE: This is a multicenter study. Patients are stratified according to number of positive lymph nodes\* (1-3 vs 4 or more) and concurrent regular low-dose of aspirin (yes vs no). Patients are randomized to 1 of 4 treatment arms. Please see the "Arms" section for more information. In all arms, treatment with celecoxib or placebo continues for 3 years in the absence of disease progression or unacceptable toxicity. Blood and tissue samples maybe collected for biomarker analysis and pharmacogenomic studies. The primary and secondary objectives for the research study are described below. Primary objective: 1\. To compare disease-free survival of patients with stage III colon cancer randomized to standard chemotherapy only FOLFOX or standard chemotherapy FOLFOX with 3 years of celecoxib 400 mg daily. Secondary objectives: 1. To contribute to an international prospective pooled analysis that will compare disease-free survival of patients with stage III colon cancer randomized to 6 treatments of adjuvant FOLFOX chemotherapy or 12 treatments of adjuvant FOLFOX chemotherapy. 2. To compare overall survival of patients with stage III colon cancer randomized to standard chemotherapy only (FOLFOX) or standard chemotherapy (FOLFOX) with 3 years of celecoxib 400 mg daily. 3. To contribute to an international prospective pooled analysis that will compare overall survival of patients with stage III colon cancer randomized to 6 treatments of adjuvant FOLFOX chemotherapy or 12 treatments of adjuvant FOLFOX chemotherapy or 12 treatments of adjuvant FOLFOX chemotherapy. 4. To assess toxicities of celecoxib as maintenance adjuvant therapy in patients with stage III colon cancer. 5. To assess differences in cardiovascular-specific events with celecoxib versus placebo in a population of stage III colon cancer survivors. 6. To evaluate differences in toxicities, particularly cumulative peripheral neuropathy, for patients treated with 6 treatments of FOLFOX compared to those treated with 12 treatments of FOLFOX. After completion of study therapy, patients are followed up every 6 months for up to 6 years.
Interventions
DRUGcelecoxib
Patients receive celecoxib 400 mg administered by mouth, once daily.
DRUG5-fluorouracil
Patients receive 400 mg/m\^2 intravenous bolus then 2400 mg/m\^2 continuous intravenous infusion over 46-48 hours.
OTHERplacebo
Patients receive placebo administered by mouth, once daily.
DRUGoxaliplatin
Patients receive 85 mg/m\^2 intravenous over two hours.
DRUGleucovorin
Patients receive 400 mg/m\^2 intravenous over two hours.
Sponsors
Alliance for Clinical Trials in Oncology
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Requirements for tumor parameters 1. Histologically documented adenocarcinoma of the colon. The gross inferior (caudad) margin of the primary tumor must lie above the peritoneal reflection (i.e., patients with rectal cancer are not eligible). Surgeon confirmation that the entire tumor was above the peritoneal reflection is only required in cases where it is important to establish if the tumor is a rectal or colon primary. 2. Tumors must have been completely resected. In patients with tumor adherent to adjacent structures, en bloc R0 resection must be documented in the operative report or otherwise confirmed by the surgeon. Near or positive radial margin are not exclusions as long as en bloc resection was performed. Positive proximal margin or distal margin is an exclusion. 3. Node positive disease (N1 or N2) as designated in AJCC version 7. Either at least one pathologically confirmed positive lymph node or N1C (defined as tumor deposit(s) in the subserosa, mesentery, or nonperitonealized pericolic or perirectal tissues without regional lymph node metastases). Patients with resected stage IV disease are not eligible. 4. No evidence of residual involved lymph node disease or metastatic disease at the time of registration. 5. Patients with synchronous colon cancers are eligible and staging for stratification will be based on higher N stage of the more advanced primary tumor. However, patients with synchronous colon and rectal primary tumors are not eligible. 2. NSAID use Patients are ineligible if they plan on regular use of NSAIDs at any dose more than 2 times per week (on average) or aspirin at more than 325 mg at least three times per week, on average. Low-dose aspirin not exceeding 100 mg/day is permitted. Patients who agree to stop regular NSAIDs or higher dose aspirin are eligible and no was out period is required. 3. Patient history 1. No previous or concurrent malignancy, except treated basal cell or squamous cell cancer of skin, treated in situ cervical cancer, treated lobular or ductal carcinoma in situ in one breast, or any other cancer for which the patient has been disease-free for at least 5 years. 2. No neurosensory or neuromotor toxicity ≥ grade 2 at the time of registration. 3. No known allergy to platinum compounds. 4. No prior allergic reaction or hypersensitivity to sulfonamides, celecoxib or NSAIDs. 5. No history of upper gastrointestinal ulceration, upper gastrointestinal bleeding, or upper gastrointestinal perforation within the past 3 years. Patients with ulceration, bleeding or perforation in the lower bowel are not excluded. 6. No symptomatic pulmonary fibrosis or interstitial pneumonitis ≥ grade 2. 7. No cardiac risk factors including: * Uncontrolled high blood pressure (systolic blood pressure \> 150). * Unstable angina. * History of documented myocardial infarction or cerebrovascular accident. * New York Heart Association class III or IV heart failure. 4. Pregancy/nursing status Non-pregnant and not nursing. Men and women of childbearing potential must agree to employ adequate contraception for the duration of chemotherapy and for as many as 8 weeks after the completion of chemotherapy due to the unknown teratogenic effects of FOLFOX on the developing fetus. 5. Age and performance status 1. ECOG performance status 0, 1 or 2. 2. Age at least 18 years. 6. Required initial laboratory values 1. Granulocytes ≥ 1,500/μL 2. Platelet count ≥ 100,000/μL 3. Creatinine ≤ 1.5 times upper limit of normal (ULN) 4. Total Bilirubin ≤ 1.5 times ULN in the absence of Gilbert's disease 5. Direct bilirubin ≤ 1.5 x upper limit of normal for patients with Gilbert's syndrome
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease-free Survival | At 3 years of follow-up | Disease-Free Survival (DFS) is defined as the time of randomization until documented progression or death from any cause. The endpoint of this trial is to compare disease-free survival of patients with stage III colon cancer randomized to standard chemotherapy only (FOLFOX; Arm A and Arm C) or standard chemotherapy (FOLFOX) with 3 years of celecoxib 400 mg daily (Arm B and Arm D). The percentage of patients who were alive and disease free after 3 years are reported here. A log-rank test stratified with the stratification factors was used to compare disease-free survival (celecoxib vs placebo) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | up to 3 years from registration | Overall Survival (DFS) is defined as the time of randomization until documented death from any cause. The endpoint is to compare overall survival of patients with stage III colon cancer randomized to standard chemotherapy only (FOLFOX; Arm A and Arm C) or standard chemotherapy (FOLFOX) with 5 years of celecoxib 400 mg daily (Arm B and Arm D). The percentage of patients who were alive after 3 years are reported here. |
Countries
Canada, Puerto Rico, United States
Contacts
STUDY_CHAIRJeffrey Meyerhardt, MD, MPH
Dana-Farber Cancer Institute
Participant flow
Pre-assignment details
One patient withdrew from the trial before being randomized and was excluded from any analysis.
Participants by arm
| Arm | Count |
|---|---|
| Arm A - FOLFOX and Placebo (12 Treatments) The FOLFOX regimen consisted of every 2 weeks cycles for 12 cycles of 2-hour infusions of oxaliplatin at 85 mg/m2 and leucovorin at 400 mg/m2, followed by a bolus infusion of 400-mg/m2 of fluorouracil following by 46-48-hour continuous infusion of 2400-mg/m2 of fluorouracil.\> Placebo was dosed at 400 mg orally daily, starting by day 1 of the second treatment of FOLFOX. Placebo was administered daily for 3 years from the date of initiation of the first dose or until recurrence of disease or unacceptable toxicity. | 615 |
| Arm B - 12 Cycles of FOLFOX Plus Celecoxib Daily The FOLFOX regimen consisted of every 2 weeks cycles for 12 cycles of 2-hour infusions of oxaliplatin at 85 mg/m2 and leucovorin at 400 mg/m2, followed by a bolus infusion of 400-mg/m2 of fluorouracil following by 46-48-hour continuous infusion of 2400-mg/m2 of fluorouracil.\> Celecoxib was dosed at 400 mg orally daily, starting by day 1 of the second treatment of FOLFOX. Celecoxib was administered daily for 3 years from the date of initiation of the first dose or until recurrence of disease or unacceptable toxicity. | 646 |
| Arm C - 6 Cycles of FOLFOX Plus Placebo Daily The FOLFOX regimen consisted of every 2 weeks cycles for 6 cycles of 2-hour infusions of oxaliplatin at 85 mg/m2 and leucovorin at 400 mg/m2, followed by a bolus infusion of 400-mg/m2 of fluorouracil following by 46-48-hour continuous infusion of 2400-mg/m2 of fluorouracil.\> Placebo was dosed at 400 mg orally daily, starting by day 1 of the second treatment of FOLFOX. Placebo was administered daily for 3 years from the date of initiation of the first dose or until recurrence of disease or unacceptable toxicity. | 646 |
| Arm D - 6 Cycles of FOLFOX Plus Celecoxib Daily The FOLFOX regimen consisted of every 2 weeks cycles for 6 cycles of 2-hour infusions of oxaliplatin at 85 mg/m2 and leucovorin at 400 mg/m2, followed by a bolus infusion of 400-mg/m2 of fluorouracil following by 46-48-hour continuous infusion of 2400-mg/m2 of fluorouracil.\> Celecoxib was dosed at 400 mg orally daily, starting by day 1 of the second treatment of FOLFOX. Celecoxib was administered daily for 3 years from the date of initiation of the first dose or until recurrence of disease or unacceptable toxicity. | 617 |
| Total | 2,524 |
Baseline characteristics
| Characteristic | Arm A - FOLFOX and Placebo (12 Treatments) | Total | Arm D - 6 Cycles of FOLFOX Plus Celecoxib Daily | Arm C - 6 Cycles of FOLFOX Plus Placebo Daily | Arm B - 12 Cycles of FOLFOX Plus Celecoxib Daily |
|---|---|---|---|---|---|
| Age, Continuous | 61.0 years | 61.3 years | 61.5 years | 61.0 years | 61.9 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 42 Participants | 191 Participants | 49 Participants | 55 Participants | 45 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 559 Participants | 2268 Participants | 552 Participants | 571 Participants | 586 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 14 Participants | 65 Participants | 16 Participants | 20 Participants | 15 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants | 15 Participants | 4 Participants | 3 Participants | 5 Participants |
| Race (NIH/OMB) Asian | 22 Participants | 107 Participants | 32 Participants | 21 Participants | 32 Participants |
| Race (NIH/OMB) Black or African American | 82 Participants | 319 Participants | 73 Participants | 76 Participants | 88 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 6 Participants | 0 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 7 Participants | 1 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 20 Participants | 73 Participants | 19 Participants | 19 Participants | 15 Participants |
| Race (NIH/OMB) White | 487 Participants | 1997 Participants | 488 Participants | 522 Participants | 500 Participants |
| Region of Enrollment Canada | 57 participants | 232 participants | 61 participants | 70 participants | 44 participants |
| Region of Enrollment United States | 558 participants | 2292 participants | 556 participants | 576 participants | 602 participants |
| Sex: Female, Male Female | 265 Participants | 1134 Participants | 276 Participants | 296 Participants | 297 Participants |
| Sex: Female, Male Male | 350 Participants | 1390 Participants | 341 Participants | 350 Participants | 349 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 10 / 615 | 8 / 647 | 10 / 646 | 9 / 618 |
| other Total, other adverse events | 574 / 615 | 615 / 647 | 618 / 646 | 589 / 618 |
| serious Total, serious adverse events | 77 / 615 | 93 / 647 | 72 / 646 | 78 / 618 |
Outcome results
Primary
Disease-free Survival
Disease-Free Survival (DFS) is defined as the time of randomization until documented progression or death from any cause. The endpoint of this trial is to compare disease-free survival of patients with stage III colon cancer randomized to standard chemotherapy only (FOLFOX; Arm A and Arm C) or standard chemotherapy (FOLFOX) with 3 years of celecoxib 400 mg daily (Arm B and Arm D). The percentage of patients who were alive and disease free after 3 years are reported here. A log-rank test stratified with the stratification factors was used to compare disease-free survival (celecoxib vs placebo)
Time frame: At 3 years of follow-up
Population: All patients that were randomized and evaluable were included in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FOLFOX and Placebo (Arms A +C) | Disease-free Survival | 73.4 percentage of participants |
| FOLFOX Plus Celecoxib Daily (Arms B + D) | Disease-free Survival | 76.3 percentage of participants |
p-value: 0.1295% CI: [0.76, 1.03]Log Rank
Secondary
Overall Survival
Overall Survival (DFS) is defined as the time of randomization until documented death from any cause. The endpoint is to compare overall survival of patients with stage III colon cancer randomized to standard chemotherapy only (FOLFOX; Arm A and Arm C) or standard chemotherapy (FOLFOX) with 5 years of celecoxib 400 mg daily (Arm B and Arm D). The percentage of patients who were alive after 3 years are reported here.
Time frame: up to 3 years from registration
Population: All patients that were randomized and evaluable were included in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FOLFOX and Placebo (Arms A +C) | Overall Survival | 81.6 percentage of participants |
| FOLFOX Plus Celecoxib Daily (Arms B + D) | Overall Survival | 84.3 percentage of participants |