Colorectal Cancer
Conditions
Brief summary
The purpose of this study is to evaluate the safety and effectiveness of the bevacizumab and capecitabine combination in frail patients with untreated metastatic colorectal cancer.
Detailed description
The study will evaluate the tolerability, safety, and feasibility of combination bevacizumab and capecitabine in a small number of frail patients with metastatic colorectal cancer who have a compromised performance status. Preclinical studies suggest that the combination of chemotherapy and anti-angiogenic therapy offer an increased anti-tumor effect compared with either treatment alone.
Interventions
1000mg/m\^2 administered orally twice daily for two weeks followed by one week rest period
DRUGBevacizumab
7.5 mg/kg IV will be administered every 3 weeks
Sponsors
Genentech, Inc.
Translational Oncology Research International
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically proven adenocarcinoma of the colon at first diagnosis * Stage IV disease, with at least one measurable lesion according to the RECIST criteria * Eastern Cooperative Oncology Group (ECOG) performance status 2 * No prior chemotherapy for metastatic colorectal cancer * Prior adjuvant chemotherapy is permitted. * At least 28 days since prior surgery * If female of childbearing potential, pregnancy test is negative and willing to use effective contraception while on treatment and for at least 3 months thereafter. * Required laboratory values: * Absolute neutrophil count \> 1.5 x 10\^9/L * Hemoglobin \> 9.0 g/dL * Platelet count \> 100 x 10\^9/L * Creatinine \< 2.0 mg/dL * Total bilirubin \< 1.5 x upper limit of normal (ULN) (Patients with documented Gilbert's syndrome are eligible.) * Alkaline phosphatase and AST/ALT within the following parameters. In determining eligibility, the more abnormal of the two values (AST or ALT) should be used: * Alkaline phosphate and AST/ALT \< or = ULN * Alkaline phosphate \> 1x but \< or = 2.5x and AST/ALT \< or = ULN * Alkaline phosphate \> 2.5x but \< or = 5x and AST/ALT \< or = ULN * Alkaline phosphate \< or = ULN and AST/ALT \> 1x but \< or = 1.5x * Alkaline phosphate \> 1x but \< or = 2.5 x and AST/ALT \> 1x but \< or = 1.5x * Alkaline phosphate \< or = ULN and AST/ALT \> 1x but \< or = 2.5x
Exclusion criteria
* Prior chemotherapy for metastatic colorectal cancer * Prior treatment with an anti-angiogenic agent * Concurrent therapy with any other non-protocol anti-cancer therapy * Current or prior history of central nervous system or brain metastases * Presence of neuropathy \> grade 2 (NCI-Common Toxicity Criteria (CTC) version 3.0) at baseline * Presence of any non-healing wound, fracture, or ulcer, or the presence of clinically significant (\> grade 2) peripheral vascular disease * History of any other malignancy within the past 5 years, with the exception of non-melanoma skin cancer or carcinoma-in-situ of the cervix * Clinically significant cardiovascular disease (e.g., blood pressure \[BP\] \> 150/100, myocardial infarction or stroke within the past 6 months, unstable angina, New York Heart Association (NYHA) Grade II or greater congestive heart failure, or serious cardiac arrhythmia requiring medication * Active peptic ulcer disease, inflammatory bowel disease, or other gastrointestinal condition increasing the risk of perforation; history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days prior to beginning therapy * Active infection requiring parenteral antimicrobials * The presence of any other medical or psychiatric disorder that, in the opinion of the treating physician, would contraindicate the use of the drugs in this protocol or place the subject at undue risk for treatment complications * Inability to comply with the study protocol or follow-up procedures * Pregnancy or lactation * A history of a severe hypersensitivity reaction to bevacizumab, or capecitabine or other drugs formulated with polysorbate 80. * Evidence of bleeding diathesis or coagulopathy. * Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 0, or anticipation of the need for a major surgical procedure during the course of the study; minor surgical procedure, fine needle aspiration or core biopsy within 7 days prior to Day 0 * Current, recent (within 4 weeks of the first infusion of this study), or planned participation in an experimental drug study other than a Genentech-sponsored bevacizumab cancer study * Unstable angina * Urine protein creatinine ratio greater than or equal to 1. * Therapeutic anticoagulation with oral anticoagulation medications, specifically coumarins
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Disease Progression | 12 months | Progression Free Survival (PFS)- the interval from the date of enrollment to the first documented date of disease progression, death due to cancer, or the last date of a definitive assessment (not an unknown assessment) at which the patient is known to be progression-free. If there is an unknown assessment, then (a) if the next subsequent definitive assessment is complete response (CR), partial response (PR), or stable disease (SD), the patient is considered to be progression-free at the date of the subsequent definitive assessment and PFS is calculated as above; (b) if the next subsequent definitive assessment is progressive disease (PD), the patient is considered to be a failure at the time of the (earliest) assessment of unknown preceding the documented disease progression (i.e. PFS is back-dated to the date of the unknown assessment) and (c) if there is no subsequent definitive assessment, PFS for the patient is considered to be a censored observation at the date |
| Number of Subjects Requiring Dose Modifications | 3 months | Number of Subjects that required Bevacizumab or Capecitabine dose modifications, delay, reduction or discontinuation due to adverse reactions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Response Rates | every 21 days up to 12 months | Evaluation of target lesions Complete Response (CR): Disappearance of all target lesions Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (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 |
| Quality of Life of Patients | Baseline, Cycle 2, and End of Study | Functional Assessment of Cancer Therapy-Colorectal (FACT-C) Trial Outcome Index (TOI) - a questionnaire assessing quality of life concerns pertinent to colorectal cancer patients. Questions address Physical, Emotional and Functional Well-Being. Scale: Not at all (0), A little bit (1), Somewhat (2), Quite a bit (3), and very much (4). Higher numbers indicate a better state of well being. Scale 0 -136. Higher numbers indicating a better state of well-being. The Overall scores for the FACT-C Composite scale range between 0-100 with higher scores indicating a better state of well being. The EQ VAS= Euro Quality of Life 5 Dimension Self Reported Healthstate. It records the respondent's self-rated health on a vertical, visual analogue scale where the endpoints are labeled 0 'Best imaginable health state' and 100 'Worst imaginable health state'. |
Countries
United States
Participant flow
Recruitment details
Dates of recruitment period: October 2005 to February 2009 Types of location: Academic medical oncology clinical and community medical oncology clinics
Participants by arm
| Arm | Count |
|---|---|
| Bevacizumab Plus Capecitabine Bevacizumab 7.5 mg/kg every 3 weeks will be administered interavenously (IV) to the enrolled patients. Oral capecitabine 1000 mg/m\^2 twice daily for 14 days followed by 7 days off every 21 days. Treatment will continue until disease progression, unacceptable toxicity, or withdrawal of patient consent. | 45 |
| Total | 45 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Follow-up | Progressive Disease | 4 |
Baseline characteristics
| Characteristic | Bevacizumab Plus Capecitabine |
|---|---|
| Age, Continuous | 79 years |
| Eastern Cooperative Oncology Group (ECOG) Score of 1 | 17 subjects |
| Eastern Cooperative Oncology Group (ECOG) Score of 2 | 28 subjects |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 36 Participants |
| Region of Enrollment United States | 45 participants |
| Sex: Female, Male Female | 27 Participants |
| Sex: Female, Male Male | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 30 / 45 |
| serious Total, serious adverse events | 45 / 45 |
Outcome results
Primary
Number of Subjects Requiring Dose Modifications
Number of Subjects that required Bevacizumab or Capecitabine dose modifications, delay, reduction or discontinuation due to adverse reactions.
Time frame: 3 months
Population: all subjects that received chemotherapy
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bevacizumab Plus Capecitabine | Number of Subjects Requiring Dose Modifications | Delay in Bevacizumab Dose | 15 participants |
| Bevacizumab Plus Capecitabine | Number of Subjects Requiring Dose Modifications | Discontinuation of Bevacizumab | 14 participants |
| Bevacizumab Plus Capecitabine | Number of Subjects Requiring Dose Modifications | Delay in Capec itabineDose | 8 participants |
| Bevacizumab Plus Capecitabine | Number of Subjects Requiring Dose Modifications | Reduction of Capecitabine Dose | 13 participants |
| Bevacizumab Plus Capecitabine | Number of Subjects Requiring Dose Modifications | Discontinuation of Capecitabine | 16 participants |
Primary
Time to Disease Progression
Progression Free Survival (PFS)- the interval from the date of enrollment to the first documented date of disease progression, death due to cancer, or the last date of a definitive assessment (not an unknown assessment) at which the patient is known to be progression-free. If there is an unknown assessment, then (a) if the next subsequent definitive assessment is complete response (CR), partial response (PR), or stable disease (SD), the patient is considered to be progression-free at the date of the subsequent definitive assessment and PFS is calculated as above; (b) if the next subsequent definitive assessment is progressive disease (PD), the patient is considered to be a failure at the time of the (earliest) assessment of unknown preceding the documented disease progression (i.e. PFS is back-dated to the date of the unknown assessment) and (c) if there is no subsequent definitive assessment, PFS for the patient is considered to be a censored observation at the date
Time frame: 12 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab Plus Capecitabine | Time to Disease Progression | 6.87 months |
Secondary
Quality of Life of Patients
Functional Assessment of Cancer Therapy-Colorectal (FACT-C) Trial Outcome Index (TOI) - a questionnaire assessing quality of life concerns pertinent to colorectal cancer patients. Questions address Physical, Emotional and Functional Well-Being. Scale: Not at all (0), A little bit (1), Somewhat (2), Quite a bit (3), and very much (4). Higher numbers indicate a better state of well being. Scale 0 -136. Higher numbers indicating a better state of well-being. The Overall scores for the FACT-C Composite scale range between 0-100 with higher scores indicating a better state of well being. The EQ VAS= Euro Quality of Life 5 Dimension Self Reported Healthstate. It records the respondent's self-rated health on a vertical, visual analogue scale where the endpoints are labeled 0 'Best imaginable health state' and 100 'Worst imaginable health state'.
Time frame: Baseline, Cycle 2, and End of Study
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bevacizumab Plus Capecitabine | Quality of Life of Patients | Baseline FACT-C Trial outcome index (TOI) | 62.85 score on a scale | Standard Deviation 12.12 |
| Bevacizumab Plus Capecitabine | Quality of Life of Patients | Cycle 2 FACT-C TOI | 66.31 score on a scale | Standard Deviation 10.32 |
| Bevacizumab Plus Capecitabine | Quality of Life of Patients | End of Study FACT-C TOI | 62.09 score on a scale | Standard Deviation 12.12 |
| Bevacizumab Plus Capecitabine | Quality of Life of Patients | Baseline FACT-C Composite | 99.87 score on a scale | Standard Deviation 19.87 |
| Bevacizumab Plus Capecitabine | Quality of Life of Patients | Cycle 2 FACT-C Composite | 105.38 score on a scale | Standard Deviation 17.02 |
| Bevacizumab Plus Capecitabine | Quality of Life of Patients | End of Study FACT-Composite | 98.61 score on a scale | Standard Deviation 21.73 |
| Bevacizumab Plus Capecitabine | Quality of Life of Patients | Baseline EQ-5D VAS | 61.76 score on a scale | Standard Deviation 23.17 |
| Bevacizumab Plus Capecitabine | Quality of Life of Patients | Cycle 2 EQ-5D VAS | 68.59 score on a scale | Standard Deviation 22.26 |
| Bevacizumab Plus Capecitabine | Quality of Life of Patients | End of Study EQ-5D VAS | 66.54 score on a scale | Standard Deviation 23.18 |
Secondary
Response Rates
Evaluation of target lesions Complete Response (CR): Disappearance of all target lesions Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (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: every 21 days up to 12 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bevacizumab Plus Capecitabine | Response Rates | Complete Response | 2 participants |
| Bevacizumab Plus Capecitabine | Response Rates | Partial Response | 14 participants |
| Bevacizumab Plus Capecitabine | Response Rates | Stable Disease | 16 participants |
| Bevacizumab Plus Capecitabine | Response Rates | Progression | 9 participants |
| Bevacizumab Plus Capecitabine | Response Rates | Not Evaluable | 4 participants |