Capecitabine, Temozolomide, and Bevacizumab for Metastatic or Unresectable Pancreatic Neuroendocrine Tumors

• Sponsor: Shaheen Shagufta (Other)
• Overall Status: Completed
• CT.gov ID: NCT01525082
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 20
• Location: 1
• Arm: 1
• Duration (Months): 85
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this research is to evaluate the effectiveness and safety of a combination of capecitabine, temozolomide and bevacizumab in the treatment of advanced pancreatic neuroendocrine tumors.

Condition or Disease	Intervention/Treatment	Phase
Gastrinoma; Glucagonoma; Insulinoma; Pancreatic Polypeptide Tumor; Recurrent Islet Cell Carcinoma; Recurrent Pancreatic Cancer; Somatostatinoma; Stage III Pancreatic Cancer; Stage IV Pancreatic Cancer	Drug: Capecitabine; Drug: Temozolomide; Biological: Bevacizumab	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

• Estimate if the combination of capecitabine and temozolomide with bevacizumab for metastatic or unresectable neuroendocrine tumors will improve response rate (RR) by 62% over historical controls (null RR of 40% to true RR 65%).

• Assess the toxicities using Common Terminology Criteria for Adverse Events (CTCAE) v4.0.

SECONDARY OBJECTIVES:

• Evaluate progression-free survival (PFS) and overall survival (OS) using Kaplan-Meier analysis.

• Assess O6-methyl guanine-deoxyribonucleic acid (DNA) methyltransferase (MGMT) at baseline by central pathology (path) review.

• Assess serum hormone marker levels.

• Evaluate computed tomography (CT) Perfusion as a tool to predict early therapeutic response. (Optional)

• Bank serum for future correlative analyses.

OUTLINE:

Patients receive bevacizumab intravenously (IV) over 30 to 90 minutes on days 1 and 15, capecitabine orally (PO) twice daily (BID) on days 1 to 14, and temozolomide PO once daily (QD) on days 10 to 14. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity, with assessment for treatment effect every 3 cycles.

After completion of study treatment, patients are followed up patients are followed long-term for survival.

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Study of Capecitabine, Temozolomide, and Bevacizumab for Metastatic or Unresectable Pancreatic Neuroendocrine Tumors
• Study Start Date: Dec 1, 2012
• Actual Primary Completion Date: Jan 1, 2018
• Actual Study Completion Date: Dec 31, 2019

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Bevacizumab + Capecitabine + Temozolomide Cycles repeat every 28 days until disease progression, unacceptable toxicity, or withdrawal.

Drug: Capecitabine; Capecitabine by mouth twice daily on Days 1 to 14; Other Names: CAPE Ro 09-1978/000 Xeloda ; Drug: Temozolomide; Temozolomide by mouth daily on Days 10 to 14; Other Names: SCH 52365 Temodal Temodar TMZ ; Biological: Bevacizumab; Bevacizumab IV over 30 to 90 minutes on Days 1 & 15; Other Names: Avastin anti-VEGF humanized monoclonal antibody anti-VEGF monoclonal antibody rhuMAb VEGF

Outcome Measures

Primary Outcome Measures

1. Radiographic Response (RR) [18 months]

   Tumor response to treatment with the combination of capecitabine & temozolomide plus bevacizumab in patients with metastatic or unresectable pancreatic neuroendocrine tumors was assessed per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1) for target lesions. Response is defined as: Complete Response (CR) = Disappearance of all target lesions Partial Response (PR) = ≥ 30% decrease in the sum of the longest diameter of target lesions Overall Response (OR) = CR + PR Progressive disease (PD) = 20% increase in the sum of the longest diameter of target lesions, and/or the appearance of one or more new lesion(s) Stable disease (SD) = Small changes that do not meet any of the above criteria The outcome is reported as the number of participants who between 3 and 18 months after treatment initiation achieve CR, PR, or clinical response (PR + CR), each a number without dispersion.

Secondary Outcome Measures

1. Treatment-related Toxicity [18 months]

   Patients will be monitored for hematologic (blood and lymphatic), gastrointestinal (stomach and gut), renal (kidney), liver (metabolic), neurological, and systemic (constitutional) toxicities (treatment-related adverse events). Toxicity events occurring during treatment will be tabulated for each indicated organ system, and listed separated for serious and non-serious events, with the toxicity attribution indicated. The outcome is reported as the number of events, a number without dispersion.

2. Progression-free Survival (PFS) [82 months]

   Progression-free survival (PFS) means the length of time that participants survive without disease (tumor) progression, and was assessed using Kaplan-Meier analysis. The outcome is given as the mean in months with standard error of the mean.

3. Overall Survival (OS) [82 mo]

   Time from the date of enrollment to the date of death due to any cause or the last date the patient was known to be alive (censored observation) at the date of data cutoff for the final analysis. The results will be reported as median in months The length of overall survival (OS) of participants was assessed by Kaplan-Meier analysis. The outcome is given as the median in months with full range.

4. O6-methylguanine DNA Methyltransferase (MGMT) Status by Immunohistochemistry (IHC) [18 months]

   O6-alkylguanine DNA alkyltransferase is a protein that in humans is encoded by the gene "O6-methylguanine DNA methyltransferase" (MGMT). Deficiency of the gene product, ie, the protein, is refereed to as "MGMT deficiency," and is thought to be predictive of response to temozolomide and is more often associated with pancreatic NETs. MGMT status in pre-treatment biopsy specimens was to be assessed by immuno-histochemistry (IHC), and associated to best clinical response. The outcome is reported by the the number of patients that were IHC-positive (MGMT detected) or IHC-negative (MGMT not detected), and by best clinical response [ie, complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD)]. The outcome is reported as a number without dispersion.

5. O6-methylguanine DNA Methyltransferase (MGMT) by Promoter Methylation [18 months]

   O6-alkylguanine DNA alkyltransferase is a protein that in humans is encoded by the gene "O6-methylguanine DNA methyltransferase" (MGMT). Deficiency of the gene product, ie, the protein, is refered to as "MGMT deficiency," and is thought to be predictive of response to temozolomide and is more often associated with pancreatic NETs. MGMT status in pre-treatment biopsy specimens was to be assessed by extent of genetic promoter methylation (an analysis of DNA), and correlated to subject survival. MGMT status in pre-treatment biopsy specimens was to be assessed by promoter methylation assessment (PM), and associated to best clinical response. The outcome is reported by the the number of patients that were PM-positive (MGMT detected) or PM-negative (MGMT not detected), and by best clinical response [ie, complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD)]. The outcome is reported as a number without dispersion.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

INCLUSION CRITERIA

• Histologically-confirmed pancreatic neuroendocrine tumors that are moderately- or well-differentiated

• Metastatic or unresectable disease

• If prior surgical resection > 5 years before the development of metastatic disease, a separate (recent) histological or cytological confirmation of metastatic disease is required

• If there is substantial clinical ambiguity regarding the nature or source of apparent metastases, clinicians should consider biopsy of lesions to establish diagnosis of metastatic disease

• The site of previous radiotherapy, if the only site of disease, has evidence of progressive disease

• If prior sunitinib and everolimus has been administered, a 2-week wash-out period is required prior to 1st dose on this study

• If prior liver-directed therapies (ie, chemoembolization, radioembolization), target lesions in the liver have demonstrated growth since the liver-directed treatment

• If prior peptide receptor radionuclide therapy (PRRT), target lesions in the liver have demonstrated growth since the liver-directed treatment

• Low-dose aspirin (≤ 325 mg/d) may be continued in subjects at higher risk for arterial thromboembolic disease.

• Primary or metastatic tumor lesion measurable in at least 1 dimension, within 4 weeks prior to entry of study.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2

• ≥ 18 years of age.

• Laboratory values as follows, ≤ 2 weeks prior to randomization:

• Absolute neutrophil count (ANC) ≥ 1.5 x 10e9/L (≥ 1500/mm³)

• Platelets (PLT) ≥ 100 x 10e9/L (≥ 100,000/mm³)

• Hemoglobin (Hgb) ≥ 9 g/dL

• Serum creatinine ≤ 1.5 x upper limit of normal (ULN)

• Serum bilirubin ≤ 1.5 x ULN

• Aspartate aminotransferase (AST/SGOT), alanine aminotransferase (ALT/SGPT) ≤ 3.0 x ULN (≤ 5.0 x ULN if liver metastases present). Note: endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous stenting may be used to normalize the liver function tests

• Urine dipstick or urinalysis for protein, value must be 0, trace, or 1+ protein to enroll. EXCEPTION: if ≥ 2+ must check 24-hour urine protein and must be < 1 g

• Life expectancy ≥ 12 weeks

• Ability to give written informed consent according to local guidelines

• If any prior therapy-related toxicities, must have recovered from all

EXCLUSION CRITERIA Disease-Specific Exclusions

• Prior bevacizumab; fluoropyrimidines (eg, capecitabine or 5-fluorouracil, 5FU); or temozolomide

• Poorly-differentiated or high-grade pancreatic neuroendocrine tumors

• Prior full field radiotherapy ≤ 4 weeks or limited field radiotherapy ≤ 2 weeks prior to enrollment

• Diagnosis of another malignancy, unless > 3 years earlier and has been disease-free for > 6 months following the completion of curative intent therapy, specific eligibility exceptions as follows:

• Curatively-resected non-melanomatous skin cancer

• Curatively-treated cervical carcinoma in situ

• Organ-confined prostate cancer with no evidence of recurrent or progressive disease based on prostate-specific antigen (PSA) values, if hormonal therapy has been initiated or a radical prostatectomy has been performed

• Other primary solid tumor curatively treated with no known active disease present and no treatment administered for > 3 years

• Concurrent use of other investigational agents and patients who have received investigational drugs ≤ 4 weeks prior to enrollment

• Known hypersensitivity to capecitabine, temozolomide, or any component of the formulation

• Known deficiency of dihydropyrimidine dehydrogenase Bevacizumab-specific Exclusions

• Inadequately-controlled hypertension (defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure > 100 mmHg)

• Prior history of hypertensive crisis or hypertensive encephalopathy

• New York Heart Association (NYHA) Grade II or greater congestive heart failure

• History of myocardial infarction or unstable angina within 6 months prior to Day 1

• History of stroke or transient ischemic attack within 6 months prior to Day 1

• Known central nervous system (CNS) metastases

• Significant vascular disease (eg, aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Day 1

• History of hemoptysis (≥ ½ teaspoon of bright red blood per episode) within 1 month prior to Day 1

• Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation)

• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1 or anticipation of need for major surgical procedure during the course of the study

• Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to Day 1

• History of abdominal fistula or gastrointestinal perforation within 6 months prior to Day 1

• Serious, non-healing wound, active ulcer, or untreated bone fracture

• Known hypersensitivity to any component of bevacizumab General Medical Exclusions

• Inability to comply with study and/or follow-up procedures

• Current, recent (within 4 weeks of the first infusion of this study), or planned participation in an experimental drug study

• Pregnant or lactating/breast feeding

• Lack of effective contraception men or women of child-bearing potential

• Uncontrolled systemic fungal, bacterial, viral, or other infection (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment)

• Known history of HIV, HBV, or HCV

• Current, ongoing treatment with full-dose warfarin. However, patients may be on stable doses of a low-molecular weight heparin are allowed [eg, (enoxaparin (Lovenox)].

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Stanford University Medical Center	Stanford	California	United States	94305

Sponsors and Collaborators

• Shaheen Shagufta
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Shaheen Shagufta, MD, Stanford University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 25, 2014
• Informed Consent Form - Mar 24, 2020

More Information

Publications

None provided.

• Responsible Party: Shaheen Shagufta, Clinical Assistant Professor, Stanford University
• ClinicalTrials.gov Identifier: NCT01525082
• Other Study ID Numbers: IRB-22412; NCI-2011-03497; SU-10282011-8571; NET0012; END0012; 4593
• First Posted: Feb 2, 2012
• Last Update Posted: May 4, 2021
• Last Verified: Apr 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Additional relevant MeSH terms: Pancreatic Neoplasms; Neuroendocrine Tumors; Insulinoma; Carcinoma, Islet Cell; Gastrinoma; Glucagonoma; Somatostatinoma; Recurrence; Bevacizumab; Antineoplastic Agents, Immunological; Capecitabine; Temozolomide; Antibodies; Immunoglobulins; Antibodies, Monoclonal

Study Results

Participant Flow

Arm/Group Title	Bevacizumab + Capecitabine + Temozolomide
Arm/Group Description	Cycles repeat every 28 days until disease progression, unacceptable toxicity, or withdrawal. Assessments for treatment effect are after every 3 cycles of treatment. Capecitabine: Capecitabine by mouth twice daily on Days 1 to 14 Temozolomide: Temozolomide by mouth daily on Days 10 to 14 Bevacizumab: Bevacizumab IV over 30 to 90 minutes on Days 1 & 15
Period Title: Overall Study
STARTED	20
COMPLETED	19
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Bevacizumab + Capecitabine + Temozolomide
Arm/Group Description	Cycles repeat every 28 days until disease progression, unacceptable toxicity, or withdrawal. Capecitabine: Capecitabine by mouth twice daily on Days 1 to 14 Temozolomide: Temozolomide by mouth daily on Days 10 to 14 Bevacizumab: Bevacizumab IV over 30 to 90 minutes on Days 1 & 15
Overall Participants	20
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	17 85%
>=65 years	3 15%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	53.9 (10.7)
Sex: Female, Male (Count of Participants)
Female	9 45%
Male	11 55%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 10%
Not Hispanic or Latino	16 80%
Unknown or Not Reported	2 10%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	4 20%
Native Hawaiian or Other Pacific Islander	1 5%
Black or African American	0 0%
White	14 70%
More than one race	0 0%
Unknown or Not Reported	1 5%
Region of Enrollment (participants) [Number]
United States	20 100%

Outcome Measures

1. Primary Outcome

Title	Radiographic Response (RR)
Description	Tumor response to treatment with the combination of capecitabine & temozolomide plus bevacizumab in patients with metastatic or unresectable pancreatic neuroendocrine tumors was assessed per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1) for target lesions. Response is defined as: Complete Response (CR) = Disappearance of all target lesions Partial Response (PR) = ≥ 30% decrease in the sum of the longest diameter of target lesions Overall Response (OR) = CR + PR Progressive disease (PD) = 20% increase in the sum of the longest diameter of target lesions, and/or the appearance of one or more new lesion(s) Stable disease (SD) = Small changes that do not meet any of the above criteria The outcome is reported as the number of participants who between 3 and 18 months after treatment initiation achieve CR, PR, or clinical response (PR + CR), each a number without dispersion.
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

Not all participants were evaluable for response to treatment.

Arm/Group Title	Bevacizumab + Capecitabine + Temozolomide
Arm/Group Description	Cycles repeat every 28 days until disease progression, unacceptable toxicity, or withdrawal. Capecitabine: Capecitabine by mouth twice daily on Days 1 to 14 Temozolomide: Temozolomide by mouth daily on Days 10 to 14 Bevacizumab: Bevacizumab IV over 30 to 90 minutes on Days 1 & 15
Measure Participants	19
Overall response (OR)	9 45%
Complete Response (CR)	0 0%
Partial Response (PR)	9 45%
Stable Disease (SD)	9 45%
Progressive disease (PD)	1 5%

2. Secondary Outcome

Title	Treatment-related Toxicity
Description	Patients will be monitored for hematologic (blood and lymphatic), gastrointestinal (stomach and gut), renal (kidney), liver (metabolic), neurological, and systemic (constitutional) toxicities (treatment-related adverse events). Toxicity events occurring during treatment will be tabulated for each indicated organ system, and listed separated for serious and non-serious events, with the toxicity attribution indicated. The outcome is reported as the number of events, a number without dispersion.
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bevacizumab	Capecitabine	Temozolomide
Arm/Group Description	Toxicities attributed to bevacizumab	Toxicities attributed to capecitabine	Toxicities attributed to temozolomide
Measure Participants	20	20	20
Serious blood or lymphatic	1	0	0
Serious gastrointestinal	1	0	0
Serious kidney	1	0	0
Serious nervous system	1	0	0
Non-serious blood or lymphatic	1	5	8
Non-serious gastrointestinal	34	119	77
Non-serious systemic	11	59	56
Non-serious kidney	69	0	0
Non-serious metabolism	3	15	12
Non-serious nervous system	12	16	12

3. Secondary Outcome

Title	Progression-free Survival (PFS)
Description	Progression-free survival (PFS) means the length of time that participants survive without disease (tumor) progression, and was assessed using Kaplan-Meier analysis. The outcome is given as the mean in months with standard error of the mean.
Time Frame	82 months

Outcome Measure Data

Analysis Population Description

Participants lost to follow-up are not included. The data are final. Participants are not being followed for additional data or analysis.

Arm/Group Title	Bevacizumab + Capecitabine + Temozolomide
Arm/Group Description	Cycles repeat every 28 days until disease progression, unacceptable toxicity, or withdrawal. Capecitabine: Capecitabine by mouth twice daily on Days 1 to 14 Temozolomide: Temozolomide by mouth daily on Days 10 to 14 Bevacizumab: Bevacizumab IV over 30 to 90 minutes on Days 1 & 15
Measure Participants	20
Mean (Standard Error) [months]	25.2 (3.3)

4. Secondary Outcome

Title	Overall Survival (OS)
Description	Time from the date of enrollment to the date of death due to any cause or the last date the patient was known to be alive (censored observation) at the date of data cutoff for the final analysis. The results will be reported as median in months The length of overall survival (OS) of participants was assessed by Kaplan-Meier analysis. The outcome is given as the median in months with full range.
Time Frame	82 mo

Outcome Measure Data

Analysis Population Description

The data are final. Participants are not being followed for additional data or analysis.

Arm/Group Title	Bevacizumab + Capecitabine + Temozolomide
Arm/Group Description	Cycles repeat every 28 days until disease progression, unacceptable toxicity, or withdrawal. Capecitabine: Capecitabine by mouth twice daily on Days 1 to 14 Temozolomide: Temozolomide by mouth daily on Days 10 to 14 Bevacizumab: Bevacizumab IV over 30 to 90 minutes on Days 1 & 15
Measure Participants	20
Median (Full Range) [months]	49.8

5. Secondary Outcome

Title	O6-methylguanine DNA Methyltransferase (MGMT) Status by Immunohistochemistry (IHC)
Description	O6-alkylguanine DNA alkyltransferase is a protein that in humans is encoded by the gene "O6-methylguanine DNA methyltransferase" (MGMT). Deficiency of the gene product, ie, the protein, is refereed to as "MGMT deficiency," and is thought to be predictive of response to temozolomide and is more often associated with pancreatic NETs. MGMT status in pre-treatment biopsy specimens was to be assessed by immuno-histochemistry (IHC), and associated to best clinical response. The outcome is reported by the the number of patients that were IHC-positive (MGMT detected) or IHC-negative (MGMT not detected), and by best clinical response [ie, complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD)]. The outcome is reported as a number without dispersion.
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

For some participants, tissue was not collected, insufficient tissue was collected, or the tissue analysis failed (no result).

Arm/Group Title	Bevacizumab + Capecitabine + Temozolomide
Arm/Group Description	Cycles repeat every 28 days until disease progression, unacceptable toxicity, or withdrawal. Capecitabine: Capecitabine by mouth twice daily on Days 1 to 14 Temozolomide: Temozolomide by mouth daily on Days 10 to 14 Bevacizumab: Bevacizumab IV over 30 to 90 minutes on Days 1 & 15
Measure Participants	11
IHC-positive and CR	0 0%
IHC-positive and PR	2 10%
IHC-positive and SD	2 10%
IHC-positive and PD	1 5%
IHC-negative and CR	0 0%
IHC-negative and PR	4 20%
IHC-negative and SD	2 10%
IHC-negative and PD	0 0%

6. Secondary Outcome

Title	O6-methylguanine DNA Methyltransferase (MGMT) by Promoter Methylation
Description	O6-alkylguanine DNA alkyltransferase is a protein that in humans is encoded by the gene "O6-methylguanine DNA methyltransferase" (MGMT). Deficiency of the gene product, ie, the protein, is refered to as "MGMT deficiency," and is thought to be predictive of response to temozolomide and is more often associated with pancreatic NETs. MGMT status in pre-treatment biopsy specimens was to be assessed by extent of genetic promoter methylation (an analysis of DNA), and correlated to subject survival. MGMT status in pre-treatment biopsy specimens was to be assessed by promoter methylation assessment (PM), and associated to best clinical response. The outcome is reported by the the number of patients that were PM-positive (MGMT detected) or PM-negative (MGMT not detected), and by best clinical response [ie, complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD)]. The outcome is reported as a number without dispersion.
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

For some participants, tissue was not collected, insufficient tissue was collected, or the tissue analysis failed (no result).

Arm/Group Title	Bevacizumab + Capecitabine + Temozolomide
Arm/Group Description	Cycles repeat every 28 days until disease progression, unacceptable toxicity, or withdrawal. Capecitabine: Capecitabine by mouth twice daily on Days 1 to 14 Temozolomide: Temozolomide by mouth daily on Days 10 to 14 Bevacizumab: Bevacizumab IV over 30 to 90 minutes on Days 1 & 15
Measure Participants	11
PM-positive and CR	0 0%
PM-positive and PR	1 5%
PM-positive and SD	0 0%
PM-positive and PD	0 0%
PM-negative and CR	0 0%
PM-negative and PR	4 20%
PM-negative and SD	5 25%
PM-negative and PD	1 5%

Adverse Events

Time Frame	18 months
Adverse Event Reporting Description	This study is a single cohort of one combination treatment. Overall adverse events were collected and reported for the single cohort. No attempt will be made to conduct a retrospective analysis attributing adverse events per an analytical plan not defined in the protocol.
Arm/Group Title	Bevacizumab + Capecitabine + Temozolomide
Arm/Group Description	Cycles repeat every 28 days until disease progression, unacceptable toxicity, or withdrawal. Capecitabine: Capecitabine by mouth twice daily on Days 1 to 14 Temozolomide: Temozolomide by mouth daily on Days 10 to 14 Bevacizumab: Bevacizumab IV over 30 to 90 minutes on Days 1 & 15
All Cause Mortality
	Bevacizumab + Capecitabine + Temozolomide
	Affected / at Risk (%)	# Events
Total	2/20 (10%)
Serious Adverse Events
	Bevacizumab + Capecitabine + Temozolomide
	Affected / at Risk (%)	# Events
Total	20/20 (100%)
Blood and lymphatic system disorders
Anemia	1/20 (5%)	1
Blood and lymphatic system disorders - Other, specify	1/20 (5%)	1
Gastrointestinal disorders
Vomiting	2/20 (10%)	3
Dysphagia	1/20 (5%)	1
Abdominal pain	3/20 (15%)	4
Upper gastrointestinal hemorrhage	1/20 (5%)	1
Duodenal ulcer	1/20 (5%)	1
Gastrointestinal disorders - Other, specify	1/20 (5%)	1
Nausea	1/20 (5%)	1
General disorders
Fever	1/20 (5%)	1
Infections and infestations
Infections and infestations - Other, specify	1/20 (5%)	1
Lung infection	1/20 (5%)	2
Injury, poisoning and procedural complications
Vascular access complication	1/20 (5%)	1
Spinal fracture	1/20 (5%)	1
Investigations
Blood bilirubin increased	1/20 (5%)	1
Musculoskeletal and connective tissue disorders
Musculoskeletal and connective tissue disorder - Other, specify	1/20 (5%)	1
Nervous system disorders
Seizure	1/20 (5%)	1
Renal and urinary disorders
Proteinuria	1/20 (5%)	1
Acute kidney injury	1/20 (5%)	1
Other (Not Including Serious) Adverse Events
	Bevacizumab + Capecitabine + Temozolomide
	Affected / at Risk (%)	# Events
Total	20/20 (100%)
Blood and lymphatic system disorders
Anemia	7/20 (35%)	11
Blood and lymphatic system disorders - Other	1/20 (5%)	1
Cardiac disorders
Sinus bradycardia	1/20 (5%)	3
Palpitations	3/20 (15%)	5
Chest pain	3/20 (15%)	6
Ear and labyrinth disorders
Vertigo	1/20 (5%)	1
Tinnitus	3/20 (15%)	3
Ear pain	1/20 (5%)	1
Eye disorders
Watering eyes	2/20 (10%)	2
Blurred vision	1/20 (5%)	1
Gastrointestinal disorders
Nausea	17/20 (85%)	36
Vomiting	9/20 (45%)	19
Constipation	15/20 (75%)	30
Diarrhea	11/20 (55%)	39
Bloating	5/20 (25%)	8
Oral hemorrhage	8/20 (40%)	18
Hemorrhoids	1/20 (5%)	3
Mucositis oral	5/20 (25%)	9
Abdominal pain	13/20 (65%)	30
Gastric hemorrhage	1/20 (5%)	1
Dyspepsia	2/20 (10%)	4
Gastrointestinal disorders - Other	5/20 (25%)	7
Oral pain	4/20 (20%)	6
Hemorrhoidal hemorrhage	2/20 (10%)	2
Lip pain	1/20 (5%)	1
Rectal hemorrhage	2/20 (10%)	4
Toothache	2/20 (10%)	4
Dysphagia	1/20 (5%)	3
Lower gastrointestinal hemorrhage	1/20 (5%)	1
Anal pain	1/20 (5%)	1
Periodontal disease	1/20 (5%)	1
Oral dysesthesia	1/20 (5%)	2
Anal ulcer	1/20 (5%)	1
Abdominal distension	1/20 (5%)	1
General disorders
Fatigue	16/20 (80%)	57
Pain	5/20 (25%)	44
Edema limbs	7/20 (35%)	11
General disorders and administration site conditions - Other	2/20 (10%)	3
Fever	4/20 (20%)	6
Localized edema	1/20 (5%)	1
Non-cardiac chest pain	2/20 (10%)	2
Flu like symptoms	2/20 (10%)	4
Injection site reaction	1/20 (5%)	1
Infections and infestations
Upper respiratory infection	5/20 (25%)	5
Paronychia	1/20 (5%)	1
Vaginal infection	1/20 (5%)	2
Sinusitis	1/20 (5%)	1
Skin infection	1/20 (5%)	1
Urinary tract infection	1/20 (5%)	1
Gum infection	1/20 (5%)	1
Otitis media	1/20 (5%)	1
Tooth infection	1/20 (5%)	1
Injury, poisoning and procedural complications
Bruising	2/20 (10%)	3
Investigations
Alanine aminotransferase increased	13/20 (65%)	37
Aspartate aminotransferase increased	12/20 (60%)	34
Platelet count decreased	11/20 (55%)	32
Lymphocyte count decreased	12/20 (60%)	38
Blood bilirubin increased	5/20 (25%)	30
Creatinine increased	10/20 (50%)	27
Alkaline phosphatase increased	7/20 (35%)	17
White blood cell decreased	6/20 (30%)	12
Neutrophil count decreased	5/20 (25%)	12
Weight loss	2/20 (10%)	3
Activated partial thromboplastin time prolonged	1/20 (5%)	1
INR increased	1/20 (5%)	1
Weight gain	4/20 (20%)	6
Lymphocyte count increased	2/20 (10%)	2
Metabolism and nutrition disorders
Hypernatremia	5/20 (25%)	9
Hypocalcemia	6/20 (30%)	10
Anorexia	7/20 (35%)	9
Hypoalbuminemia	9/20 (45%)	17
Hyperglycemia	14/20 (70%)	61
Hypokalemia	3/20 (15%)	9
Hypoglycemia	4/20 (20%)	7
Hyponatremia	13/20 (65%)	30
Hyperkalemia	1/20 (5%)	1
Hypercalcemia	3/20 (15%)	6
Metabolism and nutrition disorders - Other, specify	1/20 (5%)	1
Dehydration	1/20 (5%)	1
Musculoskeletal and connective tissue disorders
Back pain	7/20 (35%)	15
Pain in extremity	9/20 (45%)	17
Musculoskeletal and connective tissue disorder - Other	5/20 (25%)	6
Arthritis	4/20 (20%)	8
Chest wall pain	2/20 (10%)	2
Arthralgia	3/20 (15%)	3
Bone pain	1/20 (5%)	2
Neck pain	1/20 (5%)	1
Flank pain	1/20 (5%)	1
Nervous system disorders
Dizziness	5/20 (25%)	7
Peripheral sensory neuropathy	2/20 (10%)	4
Headache	10/20 (50%)	22
Concentration impairment	1/20 (5%)	1
Peripheral motor neuropathy	1/20 (5%)	1
Dysgeusia	3/20 (15%)	6
Sinus pain	3/20 (15%)	8
Memory impairment	1/20 (5%)	1
Dysesthesia	1/20 (5%)	1
Paresthesia	1/20 (5%)	2
Presyncope	1/20 (5%)	1
Cognitive disturbance	1/20 (5%)	2
Psychiatric disorders
Depression	4/20 (20%)	5
Confusion	1/20 (5%)	1
Insomnia	1/20 (5%)	3
Renal and urinary disorders
Proteinuria	13/20 (65%)	53
Hematuria	9/20 (45%)	20
Urinary frequency	1/20 (5%)	3
Urinary tract pain	1/20 (5%)	2
Reproductive system and breast disorders
Vaginal hemorrhage	2/20 (10%)	2
Penile pain	1/20 (5%)	1
Irregular menstruation	1/20 (5%)	1
Respiratory, thoracic and mediastinal disorders
Epistaxis	16/20 (80%)	30
Nasal congestion	2/20 (10%)	5
Sore throat	1/20 (5%)	1
Cough	8/20 (40%)	10
Respiratory, thoracic and mediastinal disorders - Other	6/20 (30%)	6
Dyspnea	5/20 (25%)	11
Sneezing	2/20 (10%)	2
Hoarseness	1/20 (5%)	1
Allergic rhinitis	1/20 (5%)	1
Laryngeal inflammation	1/20 (5%)	1
Pulmonary hypertension	1/20 (5%)	1
Wheezing	1/20 (5%)	1
Skin and subcutaneous tissue disorders
Dry skin	5/20 (25%)	6
Pruritus	3/20 (15%)	6
Skin hyperpigmentation	11/20 (55%)	12
Palmar-plantar erythrodysesthesia syndrome	12/20 (60%)	28
Rash acneiform	1/20 (5%)	1
Skin and subcutaneous tissue disorders - Other	7/20 (35%)	8
Photosensitivity	1/20 (5%)	1
Rash maculo-papular	3/20 (15%)	4
Skin hypopigmentation	1/20 (5%)	1
Nail discoloration	1/20 (5%)	1
Alopecia	1/20 (5%)	1
Vascular disorders
Flushing	2/20 (10%)	2
Hypertension	15/20 (75%)	69
Superficial thrombophlebitis	1/20 (5%)	1
Thromboembolic event	1/20 (5%)	1
Hot flashes	1/20 (5%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.