Bevacizumab in Pats w/ Recurrent ST Brain Metas Who Have Failed Whole Brain Radiation Therapy

• Sponsor: Northwestern University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01898130
• Collaborator: Genentech, Inc. (Industry)
• Enrollment: 27
• Locations: 4
• Arm: 1
• Actual Duration (Months): 57.3
• Patients Per Site: 6.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is a study to evaluate a drug called bevacizumab in patients with cancer whose disease has spread to their brain. This study will not evaluate the effect of bevacizumab on the systemic solid tumor cancer. Bevacizumab is a medication and it is thought that bevacizumab may interfere with the growth of new blood vessels; therefore it might stop tumor growth and possibly shrink the tumor by keeping it from receiving nutrients and oxygen supplied by the blood vessels.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Cancer; Unspecified Adult Solid Tumor, Protocol Specific	Biological: bevacizumab; Procedure: quality-of-life assessment	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. Determine the radiographic response rate in patients with solid tumor brain metastases treated with bevacizumab.

SECONDARY OBJECTIVES:

1. Estimate the progression-free survival (PFS) rate at 6 months. II. Determine the time to progression based on magnetic resonance imaging (MRI) or computed tomography (CT) scans.

2. Determine the time to response based on radiographic imaging. IV. Determine the duration of response based on radiographic imaging. V. Determine overall survival. VI. Collect additional safety data. VII. Assess changes in quality of life using the Functional Assessment of Cancer Therapy-Brain (FACT-Br) while on treatment.

OUTLINE:

Patients receive bevacizumab intravenously (IV) over 30-90 minutes every 2 weeks. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 8 weeks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 27 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Trial of Bevacizumab in Patients With Recurrent Solid Tumor Brain Metastases Who Have Failed Whole Brain Radiation Therapy
• Actual Study Start Date: Nov 27, 2013
• Actual Primary Completion Date: Mar 23, 2017
• Actual Study Completion Date: Sep 5, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (bevacizumab) Patients receive bevacizumab IV over 30-90 minutes every 2 weeks. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Biological: bevacizumab; Given IV; Other Names: anti-VEGF humanized monoclonal antibody anti-VEGF monoclonal antibody Avastin rhuMAb VEGF ; Procedure: quality-of-life assessment; Ancillary studies; Other Names: quality of life assessment

Outcome Measures

Primary Outcome Measures

1. Objective Radiographic Tumor Response in Patients With Recurrent Solid Tumor Brain Metastases Treated With Bevacizumab [Every other cycle, starting cycle 3 (1 cycle =28 days) until off study. Range of cycles completed 1-20.]

   Radiographic Response to treatment will be assessed prior to every odd-numbered cycle using CT or MRI scans until disease progression, unacceptable toxicity as assessed by the Response Assessment in Neuro-Oncology (RANO) Criteria for target lesions. Response is defined as the number of patients with Complete Response (CR) plus those with Partial Response (PR) radiographically. Generally CR is defined as the disappearance of all target lesions and PR is defined as >=50% decrease in the sum of the longest diameter of target lesions.

Secondary Outcome Measures

1. Progression-Free Survival (PFS) at 6 Months in Patients With Recurrent Solid Tumor Brain Metastases Treated With Bevacizumab [At 6 months from treatment initiation.]

   Progression-Free Survival (PFS) will be measured as the time from the first dose to the first occurrence of progression or death for any reason. To estimate PFS, Kaplan-Meier curves will be calculated and PFS at 6 months will be determined from the progression-free survival curve. Progression is defined using Response Assessment in Neuro-Oncology Criteria (RANO), as a 25% or more increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

2. Time to Progression in Patients With Recurrent Solid Tumor Brain Metastases Treated With Bevacizumab [From treatment initiation, every 2 cycles (1 cycle = 28 days) until progressive disease. Range of cycles completed 1-20.]

   MRI or CT scans and clinical assessment will be used to measure Time to Progression which will be assessed as the time from the date of first dose to the date of first observation of progressive disease, non-reversible neurologic progression or increasing steroid requirements, or early discontinuation of treatment as assessed by the RANO Criteria in those patients that experience response.

3. Time to Response in Patients With Recurrent Solid Tumor Brain Metastases Treated With Bevacizumab [From the start of treatment every 2 cycles (1 cycle =28 days) until time of response. Range of cycles completed 1-20.]

   MRI or CT scans and clinical assessment will be used to measure Time to Response which will be assessed as the time from the date of first dose to the date of first observed tumor response in all patients that a response is observed. Response to treatment will be assessed using the Response Assessment in Neuro-Oncology (RANO) Criteria for target lesions. Response is defined as either Complete Response (CR) or a Partial Response (PR) radiographically. Generally CR is defined as the disappearance of all target lesions and PR is defined as >=50% decrease in the sum of the longest diameter of target lesions.

4. Duration of Response in Patients With Recurrent Solid Tumor Brain Metastases Treated With Bevacizumab [From documentation of response, every two cycles (1 cycle =28 days) until progressive disease. Range of cycles completed 1-20.]

   The Duration of Overall Response is measured from the time measurement criteria are met for Complete Response (CR) or Partial Response (PR) until the first date that recurrent or Progressive Disease (PD) is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). Duration of response will be based on CT or MRI scans and clinical assessment performed prior to every odd-numbered cycle to detect date of first response to study treatment until date of disease progression and assessed by the Response Assessment in Neuro-Oncology (RANO) Criteria for target lesions. Generally CR is defined as the disappearance of all target lesions, PR is defined as >=50% decrease in the sum of the longest diameter of target lesions and PD is defined as a 25% or more increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

5. Overall Survival (OS) in Patients With Recurrent Solid Tumor Brain Metastases Treated With Bevacizumab [From start of treatment until death from any cause. Median follow up of 8 months (range 1.3 to 47.9 months)]

   Overall Survival (OS) will be measured as the date of first dose of bevacizumab to the date of death from any cause. To estimate OS, Kaplan-Meier curves will be calculated and OS will be determined from the overall survival curve.

6. Toxicity of Bevacizumab in Patients With Recurrent Solid Tumor Brain Metastases [Assessed prior to every cylcle (cycle=28 days) while on treatment through 30 days post last dose. Range of cycles 1-20.]

   Adverse events (AE) will be collected at the start of every cycle and graded according NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. All AEs that are determined to be grade 3 or higher and at least possible related to bevacizumab will be reported for toxicity. In general AEs will be graded: Grade 1 - Mild: the event causes discomfort without disruption of normal daily activities. Grade 2 - Moderate: the event causes discomfort that affects normal daily activities. Grade 3 - Severe: the event makes the patient unable to perform normal daily activities or significantly affects his/her clinical status. Grade 4 - Life-threatening: the patient was at risk of death at the time of the event. Grade 5 - Fatal: the event caused death.

7. Quality of Life Assessments in Patients With Recurrent Solid Tumor Brain Metastases Treated With Bevacizumab [Baseline and at Cycle 3 (1 Cycle = 28 days).]

   Changes in quality of life will be evaluated using questionnaires (FACT-Br) at baseline (before treatment initiation) and at cycle 3. Four FACT scales were calculated. The higher the value the better the score, i.e., the better the quality of life perceived by patient. FACT-G (Fact General, possible range 0 - 108) BrCS (Brain Cancer Subscale, possible range 0 - 92) TOTAL (FACT-G + BrCS, possible range 0 - 200) TOI (Trial Outcome Index = Physical Well Being _ Functional Well Being +BrCS, possible range 0 - 148)

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Patients must have a histologically or cytologically confirmed non-central nervous system (CNS) primary solid malignancy at the time of initial diagnosis; NOTE: brain lesions are not required to have pathologic confirmation; in addition, a copy of the pathology report for the primary tumor is sufficient for registration purposes

• Patients must have radiographically-confirmed recurrent brain metastases from a solid tumor after WBRT

• Patients must have measurable or evaluable disease in the brain

• Patients must have been on a stable dose of corticosteroids >= 5 days prior to obtaining their baseline gadolinium (Gd)-MRI of brain

• Patients must have completed WBRT > 12 weeks prior to enrollment to limit cases of pseudoprogression; however if new lesions are noted < 12 weeks but > 4 weeks prior to enrollment, those patients are eligible

• Patients who underwent radiosurgery to treat a progressive lesion must have confirmation of tumor by tissue, magnetic resonance spectroscopy (MRS), magnetic resonance (MR) perfusion or positron emission tomography (PET) and the lesion must be measurable; NOTE: radiosurgery may be done to a lesion that will not be used for response evaluation and should be done > 2 weeks prior to enrollment

• Patients may be on other systemic chemotherapies if progressive CNS disease occurs while on these treatments; NOTE: new systemic chemotherapies should not be started unless required to treat systemic disease and should not start until at least 1 follow up imaging study has been performed

• Patients may have received any number of prior CNS directed therapies - there are no limitations

• Patients must have a life expectancy of >= 12 weeks

• Patients must have a Karnofsky performance score (KPS) of >= 60

• Whole blood cell (WBC) >= 3,000/ul

• Absolute neutrophil count (ANC) >= 1,500/mm^3

• Platelets >= 100,000/mm^3

• Hemoglobin >= 10 gm/dl (may be reached by transfusion)

• Serum glutamic oxaloacetic transaminase (SGOT) < 2 x upper limit of normal (ULN) (or < 5 x ULN if liver is involved)

• Bilirubin < 2 x ULN (or < 5 x ULN if liver is involved)

• Creatinine < 1.5 x ULN

• Patients of both sexes must agree to the use of barrier contraceptives throughout the duration of treatment on this trial and for 3 months after discontinuing treatment; NOTE: hormonal contraceptives are not acceptable as a sole method of contraception

• Patients must be > 4 weeks from any major surgery

• Patients NOT on warfarin must have a prothrombin time (PT)/international normalized ratio (INR) < 1.4 within 14 days prior to registration

• Patients on full-dose anticoagulants (e.g., warfarin or low molecular weight [LMW] heparin) must meet BOTH of the following criteria within 14 days prior to registration:

• No active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices)

• In-range INR (between 2 and 3) on a stable dose of oral anticoagulant or on a stable dose of LMW heparin

• Female patients of child-bearing potential must have a negative pregnancy test within 14 days prior to registration

• Patients must be willing and able to comply with study and/or follow-up procedures

• Patients must sign an informed consent prior to registration and before undergoing any study-specific procedures indicating that they are aware of the investigational nature of this study

Exclusion Criteria:

• Patients with a diagnosis of intrathoracic lung carcinoma of squamous cell histology are not eligible for participation

• Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using barrier birth control methods, are not eligible for participation

• Patients must not have baseline proteinuria within 14 days prior to registration as demonstrated by either:

• Urine protein: creatinine (UPC) ratio < 1.0 at screening, OR

• Urine dipstick for proteinuria =< 2+; NOTE: patients discovered to have >= 2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate =< 1g of protein in 24 hours to be eligible

• Patients must not have experienced any major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to registration, or be anticipated to need a major surgical procedure during the course of the study; NOTE: the exception is craniotomy

• Patients must not have experienced a core biopsy or other minor surgical procedure within 7 days prior to registration; NOTE: this excludes placement of a vascular access device

• Patients with a history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the previous 6 months are not eligible for participation

• Patients with a serious, non-healing wound, ulcer, or bone fracture are not eligible for participation due to the effects on vasculature by bevacizumab which may impair healing

• Patients known to be human immunodeficiency virus (HIV) or hepatitis B and/or C positive are not eligible for participation; NOTE: HIV and hepatitis testing is not required for study participation

• Patients with a history of any other cancer (except for non-melanoma skin cancer or carcinoma in-situ of the cervix), are not eligible for participation unless they are in complete remission and have been off of all therapy for that disease for a minimum of 3 years

• Patients receiving or participating on any other experimental agents/clinical trials are not eligible for participation

• Patients with a known hypersensitivity to any component of bevacizumab are not eligible for participation

• Patients with any significant medical illnesses or infection that, in the investigator's opinion, cannot be adequately controlled with appropriate therapy or would compromise the patient's ability to tolerate this therapy are not eligible for participation

• Patients with leptomeningeal disease are not eligible for participation

• Patients who have received previous treatment with bevacizumab for CNS disease are not eligible for participation

• Patients with inadequately controlled hypertension (defined as systolic blood pressure

150 and/or diastolic blood pressure > 100 mmHg) are not eligible for participation

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Northwestern University	Chicago	Illinois	United States	60611
2	Northwestern Memorial Hospital: Lake Forest Hospital	Lake Forest	Illinois	United States	60045
3	Cadence Health - CDH	Warrenville	Illinois	United States	60555
4	Columbia University Medical Center	New York	New York	United States	10032

Sponsors and Collaborators

• Northwestern University
• Genentech, Inc.

Investigators

• Principal Investigator: Priya Kumthekar, Northwestern University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 6, 2019

More Information

Publications

None provided.

• Responsible Party: Northwestern University
• ClinicalTrials.gov Identifier: NCT01898130
• Other Study ID Numbers: NU 12C06; NCI-2013-00448; STU00080404
• First Posted: Jul 12, 2013
• Last Update Posted: Sep 17, 2019
• Last Verified: Mar 1, 2019

• Additional relevant MeSH terms: Neoplasm Metastasis; Bevacizumab; Antineoplastic Agents, Immunological; Antibodies; Immunoglobulins; Antibodies, Monoclonal

Study Results

Participant Flow

Recruitment Details	The study opened for accrual on October 11, 2013 with an accrual goal of up to 27 patients. The first patient started treatment November 27, 2013. The study was designed to enroll 9 patients initially and do an interim efficacy assessment. The study was closed permanently on April 24, 2017 with 27 patients enrolled.

Arm/Group Title	Treatment (Bevacizumab)
Arm/Group Description	Patients receive 10mg/kg bevacizumab IV over 30-90 minutes every 2 weeks. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Bevacizumab: Given IV Quality-of-life assessment: Ancillary studies
Period Title: Treatment
STARTED	27
Reached 1st Response/2 Cycles	24
Went on to Start Cycle 3	21
COMPLETED	21
NOT COMPLETED	6
Period Title: Treatment
STARTED	27
COMPLETED	26
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Treatment (Bevacizumab)
Arm/Group Description	Patients receive 10mg/kg bevacizumab IV over 30-90 minutes every 2 weeks. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Bevacizumab: Given IV Quality-of-life assessment: Ancillary studies
Overall Participants	27
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	22 81.5%
>=65 years	5 18.5%
Sex: Female, Male (Count of Participants)
Female	23 85.2%
Male	4 14.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	4 14.8%
Not Hispanic or Latino	23 85.2%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 3.7%
Asian	1 3.7%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	3 11.1%
White	22 81.5%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	27 100%

Outcome Measures

1. Primary Outcome

Title	Objective Radiographic Tumor Response in Patients With Recurrent Solid Tumor Brain Metastases Treated With Bevacizumab
Description	Radiographic Response to treatment will be assessed prior to every odd-numbered cycle using CT or MRI scans until disease progression, unacceptable toxicity as assessed by the Response Assessment in Neuro-Oncology (RANO) Criteria for target lesions. Response is defined as the number of patients with Complete Response (CR) plus those with Partial Response (PR) radiographically. Generally CR is defined as the disappearance of all target lesions and PR is defined as >=50% decrease in the sum of the longest diameter of target lesions.
Time Frame	Every other cycle, starting cycle 3 (1 cycle =28 days) until off study. Range of cycles completed 1-20.

Outcome Measure Data

Analysis Population Description

Not all patients treated on study were determined to be evaluable for this objective as they did not receive follow up scans after the baseline scans.

Arm/Group Title	Treatment (Bevacizumab)
Arm/Group Description	Patients receive 10mg/kg bevacizumab IV over 30-90 minutes every 2 weeks. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Bevacizumab: Given IV Quality-of-life assessment: Ancillary studies
Measure Participants	24
Count of Participants [Participants]	2 7.4%

2. Secondary Outcome

Title	Progression-Free Survival (PFS) at 6 Months in Patients With Recurrent Solid Tumor Brain Metastases Treated With Bevacizumab
Description	Progression-Free Survival (PFS) will be measured as the time from the first dose to the first occurrence of progression or death for any reason. To estimate PFS, Kaplan-Meier curves will be calculated and PFS at 6 months will be determined from the progression-free survival curve. Progression is defined using Response Assessment in Neuro-Oncology Criteria (RANO), as a 25% or more increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time Frame	At 6 months from treatment initiation.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Bevacizumab)
Arm/Group Description	Patients receive 10mg/kg bevacizumab IV over 30-90 minutes every 2 weeks. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Bevacizumab: Given IV Quality-of-life assessment: Ancillary studies
Measure Participants	24
Median (95% Confidence Interval) [percentage of patients with PFS]	46

3. Secondary Outcome

Title	Time to Progression in Patients With Recurrent Solid Tumor Brain Metastases Treated With Bevacizumab
Description	MRI or CT scans and clinical assessment will be used to measure Time to Progression which will be assessed as the time from the date of first dose to the date of first observation of progressive disease, non-reversible neurologic progression or increasing steroid requirements, or early discontinuation of treatment as assessed by the RANO Criteria in those patients that experience response.
Time Frame	From treatment initiation, every 2 cycles (1 cycle = 28 days) until progressive disease. Range of cycles completed 1-20.

Outcome Measure Data

Analysis Population Description

6 patients experienced response and were evaluable for this outcome measure

Arm/Group Title	Treatment (Bevacizumab)
Arm/Group Description	Patients receive 10mg/kg bevacizumab IV over 30-90 minutes every 2 weeks. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Bevacizumab: Given IV Quality-of-life assessment: Ancillary studies
Measure Participants	6
All Partial Response Patients	300
Clinical Partial Response	187
Radiological Partial Response	525

4. Secondary Outcome

Title	Time to Response in Patients With Recurrent Solid Tumor Brain Metastases Treated With Bevacizumab
Description	MRI or CT scans and clinical assessment will be used to measure Time to Response which will be assessed as the time from the date of first dose to the date of first observed tumor response in all patients that a response is observed. Response to treatment will be assessed using the Response Assessment in Neuro-Oncology (RANO) Criteria for target lesions. Response is defined as either Complete Response (CR) or a Partial Response (PR) radiographically. Generally CR is defined as the disappearance of all target lesions and PR is defined as >=50% decrease in the sum of the longest diameter of target lesions.
Time Frame	From the start of treatment every 2 cycles (1 cycle =28 days) until time of response. Range of cycles completed 1-20.

Outcome Measure Data

Analysis Population Description

6 patients experienced a response and were therefore evaluable for this outcome measure.

Arm/Group Title	Treatment (Bevacizumab)
Arm/Group Description	Patients receive 10mg/kg bevacizumab IV over 30-90 minutes every 2 weeks. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Bevacizumab: Given IV Quality-of-life assessment: Ancillary studies
Measure Participants	6
All Partial Response Patients	73
Clinical Partial Response	78
Radiological Partial Response	62

5. Secondary Outcome

Title	Duration of Response in Patients With Recurrent Solid Tumor Brain Metastases Treated With Bevacizumab
Description	The Duration of Overall Response is measured from the time measurement criteria are met for Complete Response (CR) or Partial Response (PR) until the first date that recurrent or Progressive Disease (PD) is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). Duration of response will be based on CT or MRI scans and clinical assessment performed prior to every odd-numbered cycle to detect date of first response to study treatment until date of disease progression and assessed by the Response Assessment in Neuro-Oncology (RANO) Criteria for target lesions. Generally CR is defined as the disappearance of all target lesions, PR is defined as >=50% decrease in the sum of the longest diameter of target lesions and PD is defined as a 25% or more increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time Frame	From documentation of response, every two cycles (1 cycle =28 days) until progressive disease. Range of cycles completed 1-20.

Outcome Measure Data

Analysis Population Description

Patients that achieved documented Complete Response or Partial Response were evaluated for this outcome measure

Arm/Group Title	Treatment (Bevacizumab)
Arm/Group Description	Patients receive 10mg/kg bevacizumab IV over 30-90 minutes every 2 weeks. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Bevacizumab: Given IV Quality-of-life assessment: Ancillary studies
Measure Participants	6
All Partial Response Patients	227
Clinical Partial Response	110
Radiological Partial Response	463

6. Secondary Outcome

Title	Overall Survival (OS) in Patients With Recurrent Solid Tumor Brain Metastases Treated With Bevacizumab
Description	Overall Survival (OS) will be measured as the date of first dose of bevacizumab to the date of death from any cause. To estimate OS, Kaplan-Meier curves will be calculated and OS will be determined from the overall survival curve.
Time Frame	From start of treatment until death from any cause. Median follow up of 8 months (range 1.3 to 47.9 months)

Outcome Measure Data

Analysis Population Description

All patients included in OS outcome measure.

Arm/Group Title	Treatment (Bevacizumab)
Arm/Group Description	Patients receive 10mg/kg bevacizumab IV over 30-90 minutes every 2 weeks. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Bevacizumab: Given IV Quality-of-life assessment: Ancillary studies
Measure Participants	27
Median (95% Confidence Interval) [Months]	8.2

7. Secondary Outcome

Title	Toxicity of Bevacizumab in Patients With Recurrent Solid Tumor Brain Metastases
Description	Adverse events (AE) will be collected at the start of every cycle and graded according NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. All AEs that are determined to be grade 3 or higher and at least possible related to bevacizumab will be reported for toxicity. In general AEs will be graded: Grade 1 - Mild: the event causes discomfort without disruption of normal daily activities. Grade 2 - Moderate: the event causes discomfort that affects normal daily activities. Grade 3 - Severe: the event makes the patient unable to perform normal daily activities or significantly affects his/her clinical status. Grade 4 - Life-threatening: the patient was at risk of death at the time of the event. Grade 5 - Fatal: the event caused death.
Time Frame	Assessed prior to every cylcle (cycle=28 days) while on treatment through 30 days post last dose. Range of cycles 1-20.

Outcome Measure Data

Analysis Population Description

All patients that receive at least one dose of bevacizumab are considered to be evaluable for toxicity outcome measure.

Arm/Group Title	Treatment (Bevacizumab)
Arm/Group Description	Patients receive 10mg/kg bevacizumab IV over 30-90 minutes every 2 weeks. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Bevacizumab: Given IV Quality-of-life assessment: Ancillary studies
Measure Participants	27
Lymphocyte Count Decreased	1 3.7%
Headache	1 3.7%
Hypertension	3 11.1%
Thromboembolic Event	1 3.7%

8. Secondary Outcome

Title	Quality of Life Assessments in Patients With Recurrent Solid Tumor Brain Metastases Treated With Bevacizumab
Description	Changes in quality of life will be evaluated using questionnaires (FACT-Br) at baseline (before treatment initiation) and at cycle 3. Four FACT scales were calculated. The higher the value the better the score, i.e., the better the quality of life perceived by patient. FACT-G (Fact General, possible range 0 - 108) BrCS (Brain Cancer Subscale, possible range 0 - 92) TOTAL (FACT-G + BrCS, possible range 0 - 200) TOI (Trial Outcome Index = Physical Well Being _ Functional Well Being +BrCS, possible range 0 - 148)
Time Frame	Baseline and at Cycle 3 (1 Cycle = 28 days).

Outcome Measure Data

Analysis Population Description

12 patients completed quality of life questionnaires at baseline and Cycle 3 and therefore are evaluable for this outcome measure.

Arm/Group Title	Treatment (Bevacizumab)
Arm/Group Description	Patients receive 10mg/kg bevacizumab IV over 30-90 minutes every 2 weeks. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Bevacizumab: Given IV Quality-of-life assessment: Ancillary studies
Measure Participants	12
Baseline FACT-G	83.0
Baseline BrCS	64.8
Baseline TOTAL	147.8
Baseline TOI	106.0
Cycle 3 FACT-G	75.9
Cycle 3 BrCS	62.8
Cycle 3 TOTAL	138.7
Cycle 3 TOI	99.4

9. Post-Hoc Outcome

Title	Response Rate in Patients With Recurrent Solid Tumor Brain Metastases Treated With Bevacizumab
Description	Response Rate is defined as all patients with Complete Response plus those with Partial Response as assessed by Response Assessment in Neuro-Oncology (RANO) Criteria of CT or MRI scans for target lesions combined with clinical assessment. Generally RANO Response definitions are as follows: CR is defined as the disappearance of all target lesions and PR is defined as >=50% decrease in the sum of the longest diameter of target lesions.
Time Frame	Every other cycle, starting cycle 3 (1 cycle =28 days) until off study. Range of cycles completed 1-20.

Outcome Measure Data

Analysis Population Description

3 patients were determined not to be evaluable for response outcome measures as they did not get follow up scans after baseline scans.

Arm/Group Title	Treatment (Bevacizumab)
Arm/Group Description	Patients receive 10mg/kg bevacizumab IV over 30-90 minutes every 2 weeks. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Bevacizumab: Given IV Quality-of-life assessment: Ancillary studies
Measure Participants	24
Count of Participants [Participants]	6 22.2%

10. Post-Hoc Outcome

Title	Progression Free Survival (PFS) in Patients With Recurrent Solid Tumor Brain Metastases Treated With Bevacizumab
Description	Progression Free Survival (PFS) is measured from the time of treatment initiation until documentation of progressive disease or death from any cause. To estimate PFS, Kaplan-Meier curves will be calculated and PFS will be determined from the progression-free survival curve. Progression is defined using Response Assessment in Neuro-Oncology Criteria (RANO), as a 25% or more increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
Time Frame	From treatment initiation and every two cycles (1 cycle = 28 days) until disease progression. Median follow up of 8 months (range 1.3 to 47.9 months).

Outcome Measure Data

Analysis Population Description

All patients evaluable for this outcome measure.

Arm/Group Title	Treatment (Bevacizumab)
Arm/Group Description	Patients receive 10mg/kg bevacizumab IV over 30-90 minutes every 2 weeks. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Bevacizumab: Given IV Quality-of-life assessment: Ancillary studies
Measure Participants	27
Median (95% Confidence Interval) [Months]	4.3

Adverse Events

Time Frame	Adverse Events were collected from the start of treatment, through 30 days post last treatment with patients being treated twice (every 14 days) in a 28 day cycle. Range of cycles completed 1-20.
Arm/Group Title	Treatment (Bevacizumab)
Arm/Group Description	Patients receive 10mg/kg bevacizumab IV over 30-90 minutes every 2 weeks. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Bevacizumab: Given IV Quality-of-life assessment: Ancillary studies
All Cause Mortality
	Treatment (Bevacizumab)
	Affected / at Risk (%)	# Events
Total	24/27 (88.9%)
Serious Adverse Events
	Treatment (Bevacizumab)
	Affected / at Risk (%)	# Events
Total	19/27 (70.4%)
Blood and lymphatic system disorders
Febrile Neutropenia	1/27 (3.7%)
Gastrointestinal disorders
Vomiting	1/27 (3.7%)
Colitis	1/27 (3.7%)
Radiation Enteritis	1/27 (3.7%)
Constipation	1/27 (3.7%)
General disorders
Death NOS (Not otherwise specified)	1/27 (3.7%)
Infections and infestations
Viral Gastroenteritis	1/27 (3.7%)
Pneumonia	1/27 (3.7%)
Viral Illness	1/27 (3.7%)
Investigations
Blood Bilirubin Increased	1/27 (3.7%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Clinical Decline	1/27 (3.7%)
Disease Progression	3/27 (11.1%)
Nervous system disorders
Headache	1/27 (3.7%)
Transient Ischemic Attack	1/27 (3.7%)
Death due to Intracranial Hemorrhage	1/27 (3.7%)
Headache	1/27 (3.7%)
Seizure	2/27 (7.4%)
Dysarthria	1/27 (3.7%)
Respiratory, thoracic and mediastinal disorders
Pleural Effusion	1/27 (3.7%)
Dyspnea	1/27 (3.7%)
Pulmonary Edema	1/27 (3.7%)
Other (Not Including Serious) Adverse Events
	Treatment (Bevacizumab)
	Affected / at Risk (%)	# Events
Total	27/27 (100%)
Blood and lymphatic system disorders
Anemia	14/27 (51.9%)
Ear and labyrinth disorders
Tinnitus	2/27 (7.4%)
Eye disorders
Blurred Vision	3/27 (11.1%)
Gastrointestinal disorders
Constipation	8/27 (29.6%)
Diarrhea	4/27 (14.8%)
Nausea	3/27 (11.1%)
Vomiting	5/27 (18.5%)
General disorders
Edema Limbs	2/27 (7.4%)
Fatigue	13/27 (48.1%)
Fever	2/27 (7.4%)
Gait Disturbance	2/27 (7.4%)
Pain	4/27 (14.8%)
Infections and infestations
Sinusitis	3/27 (11.1%)
Urinary Tract Infection	3/27 (11.1%)
Injury, poisoning and procedural complications
Fall	3/27 (11.1%)
Investigations
Activated Partial Thromboplastin Time Prolonged	2/27 (7.4%)
Alanine Aminotransferase Increased	6/27 (22.2%)
Alkaline Phosphatase Increased	8/27 (29.6%)
Aspartate Aminotransferase Increased	13/27 (48.1%)
Blood Bilirubin Increased	6/27 (22.2%)
Lymphocyte Count Decreased	20/27 (74.1%)
Neutrophil Count Decreased	5/27 (18.5%)
Platelet Count Decreased	8/27 (29.6%)
Weight Gain	2/27 (7.4%)
Weight Loss	8/27 (29.6%)
White Blood Cell Decreased	11/27 (40.7%)
Metabolism and nutrition disorders
Anorexia	5/27 (18.5%)
Hyperglycemia	20/27 (74.1%)
Hypoalbuminemia	21/27 (77.8%)
Hypocalcemia	12/27 (44.4%)
Hypoglycemia	2/27 (7.4%)
Hypokalemia	12/27 (44.4%)
Hyponatremia	19/27 (70.4%)
Musculoskeletal and connective tissue disorders
Back Pain	2/27 (7.4%)
Generalized Muscle Weakness	2/27 (7.4%)
Nervous system disorders
Amnesia	3/27 (11.1%)
Dizziness	4/27 (14.8%)
Dysarthria	2/27 (7.4%)
Dysphasia	3/27 (11.1%)
Headaches	6/27 (22.2%)
Memory Impairment	2/27 (7.4%)
Peripheral Motor Neuropathy	2/27 (7.4%)
Paresthesia	2/27 (7.4%)
Delirium	2/27 (7.4%)
Renal and urinary disorders
Hematuria	2/27 (7.4%)
Urinary Incontinence	2/27 (7.4%)
Urinary Frequency	2/27 (7.4%)
Proteinuria	4/27 (14.8%)
Respiratory, thoracic and mediastinal disorders
Cough	5/27 (18.5%)
Epistaxis	3/27 (11.1%)
Hoarseness	3/27 (11.1%)
Nasal Congestion	3/27 (11.1%)
Skin and subcutaneous tissue disorders
Alopecia	2/27 (7.4%)
Palmar-Planar Erythrodysesthesia Syndrome	2/27 (7.4%)
Pruritus	2/27 (7.4%)
Vascular disorders
Hypertension	16/27 (59.3%)

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.