Bevacizumab Plus Capecitabine (Xeloda) in Patients With Untreated Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase II Trial to Evaluate the Efficacy and Safety of Bevacizumab in Combination With Capecitabine (Xeloda) in Frail Patients With Untreated Metastatic Colorectal Cancer

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Drug: Capecitabine (Xeloda)
* Drug: Bevacizumab


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bevacizumab Plus Capecitabine<br>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. | Drug: Capecitabine (Xeloda)<br>* 1000mg/m^2 administered orally twice daily for two weeks followed by one week rest period<br>Drug: Bevacizumab<br>* 7.5 mg/kg IV will be administered every 3 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 12 months | 
| Number of Subjects Requiring Dose Modifications | Number of Subjects that required Bevacizumab or Capecitabine dose modifications, delay, reduction or discontinuation due to adverse reactions. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | every 21 days up to 12 months | 
| 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'. | Baseline, Cycle 2, and End of Study |