Colorectal Cancer
Conditions
Keywords
adenocarcinoma of the colon, recurrent colon cancer, stage IV colon cancer, adenocarcinoma of the rectum, recurrent rectal cancer, stage IV rectal cancer
Brief summary
RATIONALE: Drugs used in chemotherapy, such as capecitabine and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells. Monoclonal antibodies, such as cetuximab and 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. Cetuximab and bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving capecitabine together with cetuximab, oxaliplatin, and bevacizumab may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving capecitabine together with cetuximab, oxaliplatin, and bevacizumab works in treating patients with metastatic or recurrent colorectal cancer that cannot be removed by surgery.
Detailed description
OBJECTIVES: Primary * Determine the response rate in patients with unresectable metastatic or recurrent colorectal adenocarcinoma treated with capecitabine, cetuximab, oxaliplatin, and bevacizumab. Secondary * Determine the safety and tolerability of this regimen in these patients. * Determine the progression-free and overall survival of patients treated with this regimen. Exploratory * Determine the effect of this regimen on the angiogenesis biomarkers in these patients. * Determine the effect of this regimen on wound angiogenesis in these patients. OUTLINE: This is a multicenter study. Patients receive oral capecitabine twice daily on days 1-14. Patients will also receive cetuximab IV over 1-2 hours, oxaliplatin IV over 2 hours, and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 3 weeks in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed for 1 month. PROJECTED ACCRUAL: Approximately 45 patients will be accrued for this study.
Interventions
BIOLOGICALbevacizumab
BIOLOGICALcetuximab
DRUGcapecitabine
DRUGoxaliplatin
Sponsors
National Cancer Institute (NCI)
Herbert Hurwitz
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Histologically confirmed adenocarcinoma of the colon or rectum * Unresectable disease * Metastatic or recurrent disease * Not amenable to potentially curative treatment * No untreated leptomeningeal or brain metastases PATIENT CHARACTERISTICS: Performance status * ECOG 0-2 Life expectancy * Not specified Hematopoietic * Absolute neutrophil count ≥ 2,000/mm\^3 * Platelet count ≥ 100,000/mm\^3 * No known uncontrolled coagulopathy Hepatic * AST and ALT \< 2.5 times upper limits of normal (ULN) (5 times ULN if liver metastases are present) * Bilirubin \< 2.0 times ULN Renal * Creatinine clearance \> 40 mL/min * Urine protein negative * Urine protein:creatinine ratio \> 1 Cardiovascular * No unstable or uncontrolled hypertension (i.e., blood pressure \[BP\] \> 150/100 mm Hg despite antihypertensive therapy) * Patients who recently started or have adjusted antihypertensive medications are eligible provided BP is \< 140/90 mm Hg for ≥ 3 different measurements over 14 days * No arterial thromboembolic events within the past 6 months, including any of the following: * Transient ischemic attack * Cerebrovascular accident * Unstable angina * Myocardial infarction * Clinically significant peripheral vascular disease * No New York Heart Association class III-IV congestive heart failure * No uncontrolled symptomatic coronary artery disease or cardiac arrhythmia * No other significant uncontrolled cardiac disease Gastrointestinal * No lack of physical integrity of the upper gastrointestinal tract * No malabsorption syndrome * No inability to tolerate oral medication Immunologic * No prior severe infusion reaction to a monoclonal antibody * No history of an allergic reaction attributed to compounds of similar chemical or biologic composition to oxaliplatin, cetuximab, capecitabine, or bevacizumab * No prior unanticipated, severe reaction to fluoropyrimidine therapy or known hypersensitivity to fluoroucacil Other * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception during the study and for 3-4 months after completion of study treatment * No peripheral neuropathy ≥ grade 2 * No other malignancy within the past 5 years except adequately treated nonmelanoma skin cancer or carcinoma in situ of the cervix * No known dihydropyrimidine dehydrogenase deficiency PRIOR CONCURRENT THERAPY: Biologic therapy * No prior adjuvant bevacizumab or cetuximab * No other concurrent anticancer immunotherapy or biologic therapy Chemotherapy * At least 6 months since a prior adjuvant fluorouracil-, leucovorin calcium-, or capecitabine-based regimen * At least 12 months since prior adjuvant oxaliplatin * No prior chemotherapy for metastatic or recurrent disease Endocrine therapy * No concurrent hormonal therapy Radiotherapy * No concurrent radiotherapy Surgery * More than 4 weeks since prior major surgery and recovered * More than 6 months since vascular surgery, stenting, or angioplasty Other * At least 4 weeks since prior and no concurrent sorivudine or brivudine * More than 4 weeks since prior participation in any investigational drug study * No prior therapy that affects or targets the epidermal growth factor pathway * No concurrent cimetidine * Concurrent ranitidine, famotidine, or proton-pump inhibitors allowed * Concurrent anticoagulation therapy with full-dose anticoagulant allowed provided dose is stable for at least 2 weeks
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Response Rate (Percentage of Participants With Partial or Complete Response) | After all subjects were evaluated for restaging which occured every 9 weeks from drug initiation until disease progression, assesed up to 24 months. | Restaging scans occurred every 9 weeks from time of study drug initiation until disease progression. Disease assessment was performed and recorded according to the Response Evaluation Criteria in Solid Tumors (RECIST v.1.0) Guidelines. The definitions were: Complete response (CR)- Disappearance of all target lesions Partial response (PD)- At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD Stable disease (SD)- Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started Progressive disease (PD) - At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Safety and Tolerability | After all participants went off study drug regimine. | Number of participants with adverse events |
| Progression-free Survival | From time of treatment until documented progression or death from any cause, whichever came first, assesed up to 60 months. | Disease assessment was performed and recorded according to the Response Evaluation Criteria in Solid Tumors (RECIST v.1.0) Guidelines. Progressive disease is defined as at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. This is the average number of months participants survived without showing progressive disease. |
| Overall Survival | From time of treatment until death from any cause, assesed up to 60 months. | Average months of survival of participants after receiving study drug. |
Other
| Measure | Time frame |
|---|---|
| Effect on Angiogenesis Biomarkers | After study completion |
| Effect on Wound Angiogenesis | After study completion |
Countries
United States
Participant flow
Recruitment details
Patients were recruited between October 2005 and June 2007 in the Duke Cancer Center, Duke Oncology Network, and Wake Forest University.
Participants by arm
| Arm | Count |
|---|---|
| Capecitabine, Oxaliplatin, Bevacizumab, Cetuximab Capecitabine - oral administration of 850 mg/m2 every 12 hours on days 1-14. Oxaliplatin - IV administration of 130 mg/m2 over 2 hours on day 1 of a cycle. Bevacizumab- IV administration of 7.5 mg/kg over 30-90 minutes on day 1 of a cycle.
Cetuximab at an initial dose of 400 mg/m2 over 120 minutes and subsequently 250 mg/m2 over 60 minutes on day 1 of a cycle.
Cycles are 21 days. | 30 |
| Total | 30 |
Baseline characteristics
| Characteristic | Capecitabine, Oxaliplatin, Bevacizumab, Cetuximab |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 6 Participants |
| Age, Categorical Between 18 and 65 years | 24 Participants |
| Age Continuous | 56 years STANDARD_DEVIATION 10 |
| Region of Enrollment United States | 30 participants |
| Sex: Female, Male Female | 16 Participants |
| Sex: Female, Male Male | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 30 / 30 |
| serious Total, serious adverse events | 10 / 30 |
Outcome results
Primary
Response Rate (Percentage of Participants With Partial or Complete Response)
Restaging scans occurred every 9 weeks from time of study drug initiation until disease progression. Disease assessment was performed and recorded according to the Response Evaluation Criteria in Solid Tumors (RECIST v.1.0) Guidelines. The definitions were: Complete response (CR)- Disappearance of all target lesions Partial response (PD)- At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD Stable disease (SD)- Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started Progressive disease (PD) - At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions
Time frame: After all subjects were evaluated for restaging which occured every 9 weeks from drug initiation until disease progression, assesed up to 24 months.
Population: All subjects who received restaging scans were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Capecitabine, Oxaliplatin, Bevacizumab, Cetuximab | Response Rate (Percentage of Participants With Partial or Complete Response) | 43 percentage of participants with response |
Secondary
Overall Survival
Average months of survival of participants after receiving study drug.
Time frame: From time of treatment until death from any cause, assesed up to 60 months.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Capecitabine, Oxaliplatin, Bevacizumab, Cetuximab | Overall Survival | 18.8 months |
Secondary
Progression-free Survival
Disease assessment was performed and recorded according to the Response Evaluation Criteria in Solid Tumors (RECIST v.1.0) Guidelines. Progressive disease is defined as at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. This is the average number of months participants survived without showing progressive disease.
Time frame: From time of treatment until documented progression or death from any cause, whichever came first, assesed up to 60 months.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Capecitabine, Oxaliplatin, Bevacizumab, Cetuximab | Progression-free Survival | 10.3 months |
Secondary
Safety and Tolerability
Number of participants with adverse events
Time frame: After all participants went off study drug regimine.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Capecitabine, Oxaliplatin, Bevacizumab, Cetuximab | Safety and Tolerability | 30 participants with adverse event |
Other Pre-specified
Effect on Angiogenesis Biomarkers
Time frame: After study completion
Other Pre-specified
Effect on Wound Angiogenesis
Time frame: After study completion