Colorectal Cancer
Conditions
Keywords
stage II colon cancer, stage III colon cancer
Brief summary
RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab (Bv) may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving combination chemotherapy together with bevacizumab after surgery may kill any tumor cells that remain after surgery. It is not yet known whether giving combination chemotherapy together with bevacizumab is more effective than combination chemotherapy alone in treating colon cancer in adjuvant setting. PURPOSE: This randomized phase III trial is studying two different combination chemotherapy regimens with or without bevacizumab to compare how well they work in treating patients who have undergone surgery for high risk stage II or stage III colon cancer.
Detailed description
This was an open-label Phase III, multicenter, multinational, randomized, 3-arm study designed to evaluate the efficacy and safety of bevacizumab in combination with either intermittent fluorouracil/leucovorin with oxaliplatin (FOLFOX4) or capecitabine plus oxaliplatin (XELOX) versus FOLFOX4 regimen alone, as adjuvant chemotherapy in colon carcinoma. The treatment phase consisted of two parts of 24 weeks for a total of 48 weeks. The first part (weeks 1 to 24) consisted of treatment with either FOLFOX4, FOLFOX4 in combination with bevacizumab, or XELOX in combination with bevacizumab. The second part (weeks 25 to 48) consisted of single-agent bevacizumab for patients randomized to either bevacizumab-containing arm, but was only an observation period for patients assigned to the FOLFOX4-alone arm. Patients were to be followed for recurrence/new occurrence of colorectal cancer and survival. Patients who experienced a confirmed recurrence, occurrence of a new colorectal cancer during therapy, or experienced unacceptable toxicity were to be taken off study treatment but remain in study follow-up. Patients that came off therapy due to a confirmed recurrence/appearance of new colorectal cancer, were to be followed for survival until the end of the study follow-up period. The primary analysis was performed 36 months after the last patient has been randomized. After the primary analysis, patients continue to be followed for survival for at least a further 2 years ie, until all patients have been followed-up for at least 5 years following randomization.
Interventions
BIOLOGICALBevacizumab
Administered as an intravenous infusion over 30 - 90 minutes.
DRUGCapecitabine
Film-coated tablets
DRUG5-Fluorouracil (5-FU)
Administered as either a bolus injection or continuous intravenous infusion over 22 hours.
DRUGLeucovorin calcium
Administered as a 200 mg/m\^2 infusion over 2 hours.
DRUGOxaliplatin
Administered as an intravenous infusion over 2 hours.
Sponsors
National Cancer Institute (NCI)
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Signed written informed consent obtained prior to any study specific screening procedures. 2. Patient willing and able to comply with the protocol. 3. Age ≥ 18 years-of-age. 4. Histologically confirmed colon carcinoma, American Joint Cancer Committee/Union Internationale Contre le Cancer (AJCC/UICC) Stage II or Stage III defined as a tumor location ≥ 15 cm from the anal verge by endoscopy or above the peritoneal reflection at surgery. The patient was not to be a candidate for (neo) adjuvant radiotherapy. Note: Stage II patients were to be considered as high-risk patients fulfilling one of the following criteria: * T4 tumours, * Patients presenting with bowel obstruction or perforation, * Histological signs of vascular invasion (i.e. blood and lymphatic vessels) or perineural invasion, * Patients aged less than 50 years, * Patients with sub-optimal surgery (less than 12 nodes analyzed). 5. Curative surgery not less than 4 and not more than 8 weeks prior to randomization. 6. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. 7. Life expectancy of ≥ 5 years.
Exclusion criteria
1. Macroscopic or microscopic evidence of remaining tumour. Patients should never have had any evidence of metastatic disease (including presence of tumour cells in the ascites). The isolated finding of cytokeratin positive cells in bone marrow is not considered evidence of metastatic disease for purposes of this study. 2. Carcinoembryonic antigen \> 1.5 x upper limit of normal (ULN) after surgery (during screening period). 3. For patients with colostomy, unwilling to delay revision until at least 28 days after treatment completion. 4. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study treatment start, not fully healed wounds, or anticipation of the need for major surgical procedure during the course of the study. Any central venous access device (CVAD) for chemotherapy administration must be inserted at least 2 days prior to treatment start. 5. Previous anti-angiogenic treatment for any malignancy; cytotoxic chemotherapy, radiotherapy or immunotherapy for colon cancer. 6. Other malignancies within the last 5 years (other than curatively treated basal cell carcinoma of the skin and/or in situ carcinoma of the cervix). 7. Females with a positive or no pregnancy test (within 7 days before treatment start) unless childbearing potential can be otherwise excluded (postmenopausal i.e. amenorrheic for at least 2 years, hysterectomy or oophorectomy). 8. Lactating women. 9. Fertile women (\< 2 years after last menstruation) and men of childbearing potential not willing to use effective means of contraception. 10. History or evidence upon physical examination of central nervous disease (CNS) disease (eg, primary brain tumour, seizure not controlled with standard medical therapy, any brain metastases). 11. History of psychiatric disability judged by the investigator to be clinically significant, precluding informed consent or interfering with compliance for oral drug intake. 12. Clinically significant (ie, active) cardiovascular disease. This includes, but is not limited to, the following examples: cerebrovascular accidents (≤ 6 months prior to randomization), myocardial infarction (≤ 1 year prior to randomization), uncontrolled hypertension (\>150/100 mmHg) while receiving chronic medication, unstable angina, New York Heart Association (NYHA) Grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication, clinically significant electrocardiogram (ECG) findings (e.g. QTc ≥ 440 msecs \[male\] 460 msecs \[female\] or ≥ 2º atrioventricular block, etc.). Patients who suffer from serious cardiac arrhythmia requiring medication can enter the study only if they are considered to be in a stable condition regarding both the arrhythmia and their medication. Patients with pacemakers are allowed to enter the study only if they are considered as being in a stable condition. In case of doubt, the investigator should obtain a consultation with a local cardiologist. 13. Lack of physical integrity of the upper gastro-intestinal tract, malabsorption syndrome, or inability to take oral medication. 14. Interstitial pneumonia or extensive symptomatic fibrosis of the lungs. 15. Known peripheral neuropathy ≥ Common terminology criteria for adverse events (CTCAE) version 3.0 Grade 1. Absence of deep tendon reflexes as the sole neurological abnormality does not render the patient ineligible. 16. Organ allografts requiring immunosuppressive therapy. 17. Serious, non-healing wound, ulcer, or bone fracture. 18. Evidence of bleeding diathesis or coagulopathy. 19. Current or recent (within 10 days prior to study treatment start) use of full-dose oral or parenteral anticoagulants or thrombolytic agent for therapeutic purposes. 20. Chronic, daily treatment with high-dose aspirin (\> 325 mg/day) or clopidogrel (\> 75 mg/day). 21. Chronic treatment with corticosteroids (dose of ≥ 10 mg/day methylprednisolone equivalent) (excluding inhaled steroids). 22. Serious intercurrent infections (uncontrolled or requiring treatment). 23. Known dihydropyrimidine dehydrogenase deficiency. 24. Current or recent (within the 28 days prior to randomization) treatment with another investigational drug or participation in another investigational study. 25. Patients with known allergy to Chinese hamster ovary cell proteins or other recombinant human or humanized antibodies or to any excipients of bevacizumab formulation, platinum compounds or to any other components of the study drugs. 26. History or presence of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug or patient at high risk from treatment complications. 27. Presence of proteinuria at baseline as defined by: \- Patients with \> 1 g of protein/24 hour by a 24-hour urine collection. 28. Any laboratory values at baseline are as follows: Haematology: * Absolute neutrophil count (ANC) \< 1.5 x 109/L * Platelet count \< 100 x 10\^9/L * Haemoglobin \< 9 g/dL (may be transfused to maintain or exceed this level) * International normalized ratio (INR) \> 1.5 * Activated partial prothrombin time (APTT) ≥ 1.5 x ULN Biochemistry: * Total bilirubin \> 1.5 x ULN * aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT) \> 2.5 x ULN * Alkaline phosphatase (ALP) \> 2.5 x ULN * Serum creatinine \> 1.5 x ULN or creatinine clearance ≤ 50 mL/min (e.g. Cockcroft-Gault formula).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease-free Survival in Stage III Cancer Patients - Time to Event | From first patient randomized until the data cut-off date of 30 June 2010 (36 months after the last patient randomized). | Disease-free survival (DFS) was defined as the time from the date of randomization to the time of a recurrence, a new occurrence of colorectal cancer or death due to any cause, whichever occurred first. Patients without an event were censored at the last date the patient was known to be disease-free. Recurrence and new occurrence of colorectal cancer were based on tumor assessments made by the investigator. Patients with no tumor assessments after baseline but still alive at the time of the clinical cut-off were censored at day 1. |
| Disease-free Survival in Stage III Cancer Patients - Number of Events | From first patient randomized until the data cut-off date of 30 June 2010 (36 months after the last patient randomized). | A disease-free survival (DFS) event was composed of a recurrence, a new occurrence of colorectal cancer or death due to any cause. Recurrence and new occurrence of colorectal cancer were based on tumor assessments made by the investigator. Triggering events for DFS are reported; a patient can have both recurrence and a new occurrence of colon cancer. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival in Stage III Cancer Patients - Time to Event: Final Analysis | From first patient randomized until the final data cut-off date of 30 June 2012 (5 years after the last patient randomized). | Overall survival was defined as the time between date of randomization and date of death due to any cause. Patients not reported as having died at the time of the clinical cut-off date (30 June 2012) were censored at the date they were last known to be alive. |
| Overall Survival in Stage III Cancer Patients - Time to Event | From first patient randomized until the clinical data cut-off date of 30 June 2010 (36 months after the last patient randomized). | Overall survival was defined as the time between date of randomization and date of death due to any cause. Patients not reported as having died at the time of the analysis were censored at the date they were last known to be alive. |
| Overall Survival in Stage III Cancer Patients - Number of Events | From first patient randomized until the clinical data cut-off date of 30 June 2010 (36 months after the last patient randomized). | An overall survival event was death due to any cause. |
| Overall Survival in Stage III Cancer Patients - Number of Events: Final Analysis | From first patient randomized until the final data cut-off date of 30 June 2012 (5 years after the last patient randomized). | An overall survival event was death due to any cause. |
Countries
United States
Participant flow
Pre-assignment details
Randomization was stratified according to geographic region and disease stage (high-risk stage II or stage III N1 or stage III N2). The primary analysis population consisted of patients with Stage III disease.
Participants by arm
| Arm | Count |
|---|---|
| FOLFOX4 Weeks 1-24: Oxaliplatin was administered as an 85 mg/m\^2 intravenous infusion over 2 hours concomitantly with leucovorin as a 200 mg/m\^2 infusion over 2 hours, followed by 5-fluorouracil (5-FU), given as a 400 mg/m\^2 bolus injection, and then as a 600 mg/m\^2 continuous infusion over 22 hours. Leucovorin 200 mg/m\^2 (alone), followed by 5-FU 400 mg/m\^2 bolus injection, and 5-FU 600 mg/m\^2 continuous infusion were repeated on day 2. Cycle length was 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks).
Weeks 25-48: Observation only. | 955 |
| FOLFOX4 + Bv Weeks 1-24: Bevacizumab 5 mg/kg was administered as an intravenous infusion over 30 - 90 minutes followed by oxaliplatin, administered as an 85 mg/m\^2 intravenous infusion over 2 hours (on day 1 only) concomitantly with leucovorin, as a 200 mg/m\^2 infusion over 2 hours, followed by 5-FU, given as a 400 mg/m\^2 bolus injection, and then as a 600 mg/m\^2 continuous infusion over 22 hours. Leucovorin 200 mg/m\^2 (alone), followed by 5-FU 400 mg/m\^2 bolus injection, and 5-FU 600 mg/m\^2 continuous infusion are repeated on day 2. Cycle length is 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks).
Weeks 25-48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks). | 960 |
| XELOX+Bv Weeks 1-24: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 - 90 minutes followed by oxaliplatin administered as a 130 mg/m\^2 intravenous infusion over 2 hours (day 1 every 3 weeks) in combination with capecitabine, which was administered orally at a dose of 1000 mg/m\^2 twice daily (equivalent to a total daily dose of 2000 mg/m\^2), with first dose the evening of day 1 and last dose the morning of day 15, given as intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment), for a total of 8 cycles (24 weeks).
Weeks 25-48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks). | 952 |
| Total | 2,867 |
Baseline characteristics
| Characteristic | FOLFOX4 | FOLFOX4 + Bv | XELOX+Bv | Total |
|---|---|---|---|---|
| Age, Customized <40 | 77 participants | 74 participants | 68 participants | 219 participants |
| Age, Customized 40-65 | 603 participants | 625 participants | 588 participants | 1816 participants |
| Age, Customized >=65 | 275 participants | 261 participants | 296 participants | 832 participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 participants | 1 participants | 0 participants | 2 participants |
| Race/Ethnicity, Customized Asian | 139 participants | 115 participants | 123 participants | 377 participants |
| Race/Ethnicity, Customized Black or African American | 6 participants | 13 participants | 14 participants | 33 participants |
| Race/Ethnicity, Customized Other | 18 participants | 18 participants | 20 participants | 56 participants |
| Race/Ethnicity, Customized White | 791 participants | 813 participants | 795 participants | 2399 participants |
| Sex: Female, Male Female | 425 Participants | 473 Participants | 432 Participants | 1330 Participants |
| Sex: Female, Male Male | 530 Participants | 487 Participants | 520 Participants | 1537 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 1,112 / 1,126 | 1,127 / 1,145 | 1,117 / 1,135 |
| serious Total, serious adverse events | 226 / 1,126 | 297 / 1,145 | 284 / 1,135 |
Outcome results
Primary
Disease-free Survival in Stage III Cancer Patients - Number of Events
A disease-free survival (DFS) event was composed of a recurrence, a new occurrence of colorectal cancer or death due to any cause. Recurrence and new occurrence of colorectal cancer were based on tumor assessments made by the investigator. Triggering events for DFS are reported; a patient can have both recurrence and a new occurrence of colon cancer.
Time frame: From first patient randomized until the data cut-off date of 30 June 2010 (36 months after the last patient randomized).
Population: The primary population for efficacy analyses was the intent to treat population (ITT; all randomized patients) with stage III disease.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FOLFOX4 | Disease-free Survival in Stage III Cancer Patients - Number of Events | Death | 17 participants |
| FOLFOX4 | Disease-free Survival in Stage III Cancer Patients - Number of Events | New Occurrence | 3 participants |
| FOLFOX4 | Disease-free Survival in Stage III Cancer Patients - Number of Events | Patients with a DFS event | 237 participants |
| FOLFOX4 | Disease-free Survival in Stage III Cancer Patients - Number of Events | Recurrence | 219 participants |
| FOLFOX4 | Disease-free Survival in Stage III Cancer Patients - Number of Events | Patients without events | 718 participants |
| FOLFOX4 + Bv | Disease-free Survival in Stage III Cancer Patients - Number of Events | New Occurrence | 8 participants |
| FOLFOX4 + Bv | Disease-free Survival in Stage III Cancer Patients - Number of Events | Patients with a DFS event | 280 participants |
| FOLFOX4 + Bv | Disease-free Survival in Stage III Cancer Patients - Number of Events | Recurrence | 253 participants |
| FOLFOX4 + Bv | Disease-free Survival in Stage III Cancer Patients - Number of Events | Death | 21 participants |
| FOLFOX4 + Bv | Disease-free Survival in Stage III Cancer Patients - Number of Events | Patients without events | 680 participants |
| XELOX+Bv | Disease-free Survival in Stage III Cancer Patients - Number of Events | Patients without events | 699 participants |
| XELOX+Bv | Disease-free Survival in Stage III Cancer Patients - Number of Events | Death | 25 participants |
| XELOX+Bv | Disease-free Survival in Stage III Cancer Patients - Number of Events | Patients with a DFS event | 253 participants |
| XELOX+Bv | Disease-free Survival in Stage III Cancer Patients - Number of Events | New Occurrence | 6 participants |
| XELOX+Bv | Disease-free Survival in Stage III Cancer Patients - Number of Events | Recurrence | 223 participants |
Primary
Disease-free Survival in Stage III Cancer Patients - Time to Event
Disease-free survival (DFS) was defined as the time from the date of randomization to the time of a recurrence, a new occurrence of colorectal cancer or death due to any cause, whichever occurred first. Patients without an event were censored at the last date the patient was known to be disease-free. Recurrence and new occurrence of colorectal cancer were based on tumor assessments made by the investigator. Patients with no tumor assessments after baseline but still alive at the time of the clinical cut-off were censored at day 1.
Time frame: From first patient randomized until the data cut-off date of 30 June 2010 (36 months after the last patient randomized).
Population: The primary population for efficacy analyses was the intent to treat population (ITT; all randomized patients) with stage III disease.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FOLFOX4 | Disease-free Survival in Stage III Cancer Patients - Time to Event | NA months |
| FOLFOX4 + Bv | Disease-free Survival in Stage III Cancer Patients - Time to Event | NA months |
| XELOX+Bv | Disease-free Survival in Stage III Cancer Patients - Time to Event | NA months |
Comparison: Adjustments for multiplicity was done using a closed test procedure which tests for differences between all three treatment groups at the 5% alpha level first. Only in case of a significant result, the pair-wise comparison between the control arm and each of the bevacizumab arm will be tested, again at the 5% alpha level.p-value: 0.2024Closed test procedure
Secondary
Overall Survival in Stage III Cancer Patients - Number of Events
An overall survival event was death due to any cause.
Time frame: From first patient randomized until the clinical data cut-off date of 30 June 2010 (36 months after the last patient randomized).
Population: ITT patients with Stage III disease.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FOLFOX4 | Overall Survival in Stage III Cancer Patients - Number of Events | Patients with events | 115 participants |
| FOLFOX4 | Overall Survival in Stage III Cancer Patients - Number of Events | Patients without events | 840 participants |
| FOLFOX4 + Bv | Overall Survival in Stage III Cancer Patients - Number of Events | Patients with events | 151 participants |
| FOLFOX4 + Bv | Overall Survival in Stage III Cancer Patients - Number of Events | Patients without events | 809 participants |
| XELOX+Bv | Overall Survival in Stage III Cancer Patients - Number of Events | Patients with events | 145 participants |
| XELOX+Bv | Overall Survival in Stage III Cancer Patients - Number of Events | Patients without events | 807 participants |
Secondary
Overall Survival in Stage III Cancer Patients - Number of Events: Final Analysis
An overall survival event was death due to any cause.
Time frame: From first patient randomized until the final data cut-off date of 30 June 2012 (5 years after the last patient randomized).
Population: ITT patients with Stage III disease.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FOLFOX4 | Overall Survival in Stage III Cancer Patients - Number of Events: Final Analysis | Patients with events | 161 participants |
| FOLFOX4 | Overall Survival in Stage III Cancer Patients - Number of Events: Final Analysis | Patients without events | 794 participants |
| FOLFOX4 + Bv | Overall Survival in Stage III Cancer Patients - Number of Events: Final Analysis | Patients with events | 202 participants |
| FOLFOX4 + Bv | Overall Survival in Stage III Cancer Patients - Number of Events: Final Analysis | Patients without events | 758 participants |
| XELOX+Bv | Overall Survival in Stage III Cancer Patients - Number of Events: Final Analysis | Patients with events | 182 participants |
| XELOX+Bv | Overall Survival in Stage III Cancer Patients - Number of Events: Final Analysis | Patients without events | 770 participants |
Secondary
Overall Survival in Stage III Cancer Patients - Time to Event
Overall survival was defined as the time between date of randomization and date of death due to any cause. Patients not reported as having died at the time of the analysis were censored at the date they were last known to be alive.
Time frame: From first patient randomized until the clinical data cut-off date of 30 June 2010 (36 months after the last patient randomized).
Population: ITT patients with Stage III disease.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FOLFOX4 | Overall Survival in Stage III Cancer Patients - Time to Event | NA months |
| FOLFOX4 + Bv | Overall Survival in Stage III Cancer Patients - Time to Event | NA months |
| XELOX+Bv | Overall Survival in Stage III Cancer Patients - Time to Event | NA months |
Secondary
Overall Survival in Stage III Cancer Patients - Time to Event: Final Analysis
Overall survival was defined as the time between date of randomization and date of death due to any cause. Patients not reported as having died at the time of the clinical cut-off date (30 June 2012) were censored at the date they were last known to be alive.
Time frame: From first patient randomized until the final data cut-off date of 30 June 2012 (5 years after the last patient randomized).
Population: ITT patients with Stage III disease.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FOLFOX4 | Overall Survival in Stage III Cancer Patients - Time to Event: Final Analysis | NA months |
| FOLFOX4 + Bv | Overall Survival in Stage III Cancer Patients - Time to Event: Final Analysis | NA months |
| XELOX+Bv | Overall Survival in Stage III Cancer Patients - Time to Event: Final Analysis | NA months |