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. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some find tumor cells and kill them or carry tumor-killing substances to them. Others interfere with the ability of tumor cells to grow and spread. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving capecitabine and oxaliplatin together with bevacizumab may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving oxaliplatin and capecitabine together with bevacizumab works in treating patients with metastatic or recurrent colorectal cancer.
Detailed description
OBJECTIVES: Primary * Evaluate the response rate in patients with previously untreated metastatic colorectal cancer treated with capecitabine, oxaliplatin, and bevacizumab. Secondary * Assess time to progression (TTP), disease-free survival (DFS), and overall survival (OS) in patients treated with this regimen. * Assess the safety and tolerability of bevacizumab, oxaliplatin, and capecitabine in patients with previously untreated metastatic colorectal cancer. Exploratory * Evaluate the effect of this regimen on the biomarkers of angiogenesis. * Assess the effect of this regimen on wound angiogenesis. OUTLINE: Patients receive oral capecitabine twice daily on days 1-5 and 8-12, oxaliplatin IV over 2 hours on day 1, and bevacizumab IV over 1-1½ hours on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. PROJECTED ACCRUAL: A total of 50 patients will be accrued for this study.
Interventions
BIOLOGICALbevacizumab
10 mg/kg intravenously over 30-90 minutes on day 1
DRUGoxaliplatin
85 mg/m2 intravenously over 2 hours on day 1.
DRUGCapecitabine
Oral administration every 12 hours on days 1-5 and 8-12 1000 mg/m2 in initial cohort
Sponsors
National Cancer Institute (NCI)
Herbert Hurwitz, MD
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 documented adenocarcinoma of the colon or rectum * Metastatic or recurrent disease not amenable to potentially curative treatment (e.g., inoperable metastatic disease) * No leptomeningeal or brain metastases PATIENT CHARACTERISTICS: * ECOG performance status 0-2 * Absolute neutrophil count ≥ 2,000/mm\^3 * Platelet count ≥ 100,000/mm\^3 * AST/ALT \< 2.5 times upper limit of normal (ULN) (5 times ULN if known liver metastases) * Bilirubin \< 1.5 times ULN * Creatinine clearance \> 50 mL/min * No unstable or poorly controlled hypertension (\> 150/100 mm Hg) * Patients who have recently started or adjusted antihypertensive medications are eligible provided blood pressure is \< 140/90 mm Hg on any new regimen for at least 3 different observations over 14 days * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception during study and for at least 3-4 months after study completion * No arterial or venous thrombosis (including cerebrovascular accident) within the last 3 months * No known, existing, uncontrolled coagulopathy * No clinically significant cardiac disease * No congestive heart failure * No symptomatic coronary artery disease * No cardiac arrhythmias not well controlled with medication * No myocardial infarction within the last 12 months * No history of allergic reactions attributed to compounds of similar chemical or biologic composition to oxaliplatin, capecitabine, or bevacizumab * No history of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that might affect the interpretation of the results of the study or render the patient at high risk from treatment complications PRIOR CONCURRENT THERAPY: * At least 4 weeks since prior sorivudine or brivudine * At least 6 months since prior adjuvant treatment with fluorouracil and leucovorin calcium or a fluorouracil and leucovorin calcium-based regimen * No major surgery within 4 weeks without complete recovery * No prior chemotherapy for metastatic/recurrent disease * No cancer immunotherapy or other biologic therapy while on therapy * No radiotherapy while on study * No hormonal therapy for cancer while on study * No full-dose warfarin (INR of \> 1.5), heparin (\> 10,000 units/day), or thrombolytic agents * Allopurinol and cimetidine should be discontinued prior to starting on this regimen
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 |
|---|---|---|
| Time to Progression | From time of treatment until documented progression, 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. |
| Disease 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. |
| 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. |
| Safety and Tolerability | After all participants went off study drug regimine. | Number of participants with adverse events |
Other
| Measure | Time frame |
|---|---|
| Effect on Angiogenesis Biomarkers | After study completion |
| Effect on Wound Angiogenesis | After study completion |
Participant flow
Recruitment details
Patients were recruited between September 2003 and July 2005 in the Duke Cancer Center and Duke Oncology Network sites.
Participants by arm
| Arm | Count |
|---|---|
| Initial Cohort oxaliplatin : 85 mg/m2 intravenously over 2 hours on day 1.
Capecitabine : Oral administration every 12 hours on days 1-5 and 8-12 1000 mg/m2 in initial cohort
bevacizumab : 10 mg/kg intravenously over 30-90 minutes on day 1 | 19 |
| Second Cohort oxaliplatin : 85 mg/m2 intravenously over 2 hours on day 1.
bevacizumab : 10 mg/kg intravenously over 30-90 minutes on day 1
Capecitabine : Oral administration every 12 hours on days 1-5 and 8-12 850 mg/m2 in second cohort | 31 |
| Total | 50 |
Baseline characteristics
| Characteristic | Second Cohort | Initial Cohort | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5 Participants | 5 Participants | 10 Participants |
| Age, Categorical Between 18 and 65 years | 26 Participants | 14 Participants | 40 Participants |
| Age, Continuous | 55.3 years STANDARD_DEVIATION 12.6 | 54.6 years STANDARD_DEVIATION 13.3 | 55 years STANDARD_DEVIATION 12.8 |
| Region of Enrollment United States | 31 participants | 19 participants | 50 participants |
| Sex: Female, Male Female | 18 Participants | 5 Participants | 23 Participants |
| Sex: Female, Male Male | 13 Participants | 14 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 19 / 19 | 29 / 31 |
| serious Total, serious adverse events | 6 / 19 | 9 / 31 |
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 had restaging scans were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Initial Cohort | Response Rate (Percentage of Participants With Partial or Complete Response) | 63 percentage of participants with response |
| Second Cohort | Response Rate (Percentage of Participants With Partial or Complete Response) | 42 percentage of participants with response |
Secondary
Disease 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.
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) |
|---|---|---|
| Initial Cohort | Disease Free Survival | 10.1 months |
| Second Cohort | Disease Free Survival | 10.4 months |
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) |
|---|---|---|
| Initial Cohort | Overall Survival | 19.6 months |
| Second Cohort | Overall Survival | 24.8 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) |
|---|---|---|
| Initial Cohort | Safety and Tolerability | 19 participants with adverse event |
| Second Cohort | Safety and Tolerability | 29 participants with adverse event |
Secondary
Time to Progression
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.
Time frame: From time of treatment until documented progression, assesed up to 60 months.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Initial Cohort | Time to Progression | 10.1 months | 95% Confidence Interval 5.7 |
| Second Cohort | Time to Progression | 10.4 months | — |
Other Pre-specified
Effect on Angiogenesis Biomarkers
Time frame: After study completion
Other Pre-specified
Effect on Wound Angiogenesis
Time frame: After study completion