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

• Sponsor: Translational Oncology Research International (Other)
• Overall Status: Completed
• CT.gov ID: NCT00203411
• Collaborator: Genentech, Inc. (Industry)
• Enrollment: 45
• Locations: 12
• Arm: 1
• Duration (Months): 60
• Patients Per Site: 3.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Colorectal Cancer	Drug: Capecitabine (Xeloda); Drug: Bevacizumab	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 45 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: Mar 1, 2006
• Actual Primary Completion Date: Mar 1, 2011
• Actual Study Completion Date: Mar 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Drug: Capecitabine (Xeloda); 1000mg/m^2 administered orally twice daily for two weeks followed by one week rest period; Drug: Bevacizumab; 7.5 mg/kg IV will be administered every 3 weeks

Outcome Measures

Primary Outcome Measures

1. 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

2. 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 Outcome Measures

1. 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

2. 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'.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Central Hematology Oncology Medical Group, Inc.	Alhambra	California	United States	91801
2	Comprehensive Blood and Cancer Center	Bakersfield	California	United States	93309
3	Virginia K. Crosson Cancer Center	Fullerton	California	United States	92835
4	Pacific Shores Medical Group	Long Beach	California	United States	90813
5	UCLA Medical Center	Los Angeles	California	United States	90095
6	North Valley Hematology/Oncology Medical Group	Northridge	California	United States	91328
7	Ventura County Hematology-Oncology Specialists	Oxnard	California	United States	93030
8	Wilshire Oncology Medical Group, Inc.	Pomona	California	United States	91767
9	Cancer Care Associates Medical Group, Inc.	Redondo Beach	California	United States	90277
10	Santa Barbara Hematology Oncology Medical Group, Inc.	Santa Barbara	California	United States	93105
11	Central Coast Medical Oncology Corporation	Santa Maria	California	United States	93454
12	Comprehensive Cancer Centers of Nevada	Las Vegas	Nevada	United States	89109

Sponsors and Collaborators

• Translational Oncology Research International
• Genentech, Inc.

Investigators

• Study Chair: Arash Naeim, MD, PhD, University of California, Los Angeles
• Study Chair: Randy Hecht, MD, University of California, Los Angeles

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Translational Oncology Research International
• ClinicalTrials.gov Identifier: NCT00203411
• Other Study ID Numbers: TORI GI-04; NCT00217685
• First Posted: Sep 20, 2005
• Last Update Posted: Feb 6, 2017
• Last Verified: Mar 1, 2016

• Additional relevant MeSH terms: Colorectal Neoplasms; Bevacizumab; Capecitabine

Study Results

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

Arm/Group Title	Bevacizumab Plus Capecitabine
Arm/Group Description	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. Capecitabine (Xeloda): 1000mg/m2 administered orally twice daily for two weeks followed by one week rest period Bevacizumab: 7.5 mg/kg IV will be administered every 3 weeks
Period Title: Treatment Period
STARTED	45
COMPLETED	45
NOT COMPLETED	0
Period Title: Treatment Period
STARTED	45
COMPLETED	41
NOT COMPLETED	4

Baseline Characteristics

Arm/Group Title	Bevacizumab Plus Capecitabine
Arm/Group Description	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.
Overall Participants	45
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	79
Sex: Female, Male (Count of Participants)
Female	27 60%
Male	18 40%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	4 8.9%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	3 6.7%
White	36 80%
More than one race	0 0%
Unknown or Not Reported	2 4.4%
Region of Enrollment (participants) [Number]
United States	45 100%
Eastern Cooperative Oncology Group (ECOG) (subjects) [Number]
Score of 1	17
Score of 2	28

Outcome Measures

1. Primary Outcome

Title	Time to Disease Progression
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bevacizumab Plus Capecitabine
Arm/Group Description	Bevacizumab 7.5 mg/kg every 3 weeks will be administered intravenously (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.
Measure Participants	45
Median (95% Confidence Interval) [months]	6.87

2. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

all subjects that received chemotherapy

Arm/Group Title	Bevacizumab Plus Capecitabine
Arm/Group Description	Bevacizumab 7.5 mg/kg every 3 weeks will be administered intravenously (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.
Measure Participants	45
Delay in Bevacizumab Dose	15 33.3%
Discontinuation of Bevacizumab	14 31.1%
Delay in Capec itabineDose	8 17.8%
Reduction of Capecitabine Dose	13 28.9%
Discontinuation of Capecitabine	16 35.6%

3. Secondary Outcome

Title	Response Rates
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bevacizumab Plus Capecitabine
Arm/Group Description	Bevacizumab 7.5 mg/kg every 3 weeks will be administered intravenously (IV) to the enrolled patients. Oral capecitabine 1000 mg/m2 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.
Measure Participants	45
Complete Response	2 4.4%
Partial Response	14 31.1%
Stable Disease	16 35.6%
Progression	9 20%
Not Evaluable	4 8.9%

4. Secondary Outcome

Title	Quality of Life of Patients
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bevacizumab Plus Capecitabine
Arm/Group Description	Bevacizumab 7.5 mg/kg every 3 weeks will be administered intravenously (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.
Measure Participants	45
Baseline FACT-C Trial outcome index (TOI)	62.85 (12.12)
Cycle 2 FACT-C TOI	66.31 (10.32)
End of Study FACT-C TOI	62.09 (12.12)
Baseline FACT-C Composite	99.87 (19.87)
Cycle 2 FACT-C Composite	105.38 (17.02)
End of Study FACT-Composite	98.61 (21.73)
Baseline EQ-5D VAS	61.76 (23.17)
Cycle 2 EQ-5D VAS	68.59 (22.26)
End of Study EQ-5D VAS	66.54 (23.18)

Adverse Events

Time Frame	From time of consent evaluated every 21 days until 30 days after last treatment, up to 1 year.
Adverse Event Reporting Description	Systemic adverse event assessment occurred every through investigator assessment during the Treatment period
Arm/Group Title	Bevacizumab Plus Capecitabine
Arm/Group Description	Bevacizumab 7.5 mg/kg every 3 weeks will be administered intravenously (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.
All Cause Mortality
	Bevacizumab Plus Capecitabine
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Bevacizumab Plus Capecitabine
	Affected / at Risk (%)	# Events
Total	45/45 (100%)
Blood and lymphatic system disorders
Leukopenia	1/45 (2.2%)	1
Dyspepsia	1/45 (2.2%)	1
Gastrointestinal disorders
Diarrhea	8/45 (17.8%)	8
Dehydration	4/45 (8.9%)	4
Vomiting	3/45 (6.7%)	3
Nausea	2/45 (4.4%)	2
Mucositis	2/45 (4.4%)	2
Anorexia	2/45 (4.4%)	2
Bloating	2/45 (4.4%)	2
Hemorrhage-GI	1/45 (2.2%)	1
Obstruction	2/45 (4.4%)	2
Infarction	1/45 (2.2%)	1
General disorders
Fatigue	6/45 (13.3%)	6
Pain-Abdomen	2/45 (4.4%)	2
Hepatobiliary disorders
Liver Failure	1/45 (2.2%)	1
Renal Failure	1/45 (2.2%)	1
Nervous system disorders
Cerebral vascular accident	1/45 (2.2%)	1
Skin and subcutaneous tissue disorders
Hand Foot Skin Reaction	6/45 (13.3%)	6
Vascular disorders
Hypertension	3/45 (6.7%)	3
Deep vein thrombosis	1/45 (2.2%)	1
Other (Not Including Serious) Adverse Events
	Bevacizumab Plus Capecitabine
	Affected / at Risk (%)	# Events
Total	30/45 (66.7%)
Blood and lymphatic system disorders
Anemia	13/45 (28.9%)	13
Thrombocytopenia	8/45 (17.8%)	8
Leukopenia	7/45 (15.6%)	7
Hemorrhage-Nose	6/45 (13.3%)	6
Edema-limb	5/45 (11.1%)	5
Ear and labyrinth disorders
Dizziness	5/45 (11.1%)	5
Gastrointestinal disorders
Diarrhea	28/45 (62.2%)	28
Nausea	21/45 (46.7%)	21
Mucositis	16/45 (35.6%)	16
Anorexia	15/45 (33.3%)	15
Vomiting	9/45 (20%)	9
Dehydration	7/45 (15.6%)	7
General disorders
Fatigue	30/45 (66.7%)	30
Memory Impairment	5/45 (11.1%)	5
Metabolism and nutrition disorders
Weight Loss	5/45 (11.1%)	5
Nervous system disorders
Neuropathy	11/45 (24.4%)	11
Pain-Abdomen	10/45 (22.2%)	10
Pain-Head	5/45 (11.1%)	5
Renal and urinary disorders
Proteinuria	7/45 (15.6%)	7
Skin and subcutaneous tissue disorders
Hand Foot Skin Reaction	24/45 (53.3%)	24
Dry Skin	8/45 (17.8%)	8
Rash	7/45 (15.6%)	7
Vascular disorders
Hypertension	10/45 (22.2%)	10

Limitations/Caveats

This was a small study with only 45 participants who received study treatment. With such a small sample size the study does not have the statistical power to make categorical assessments or statements.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.