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

Unspecified Adult Solid Tumor, Protocol Specific Clinical Trial

Official title:

A Phase II Trial of Bevacizumab in Patients With Recurrent Solid Tumor Brain Metastases Who Have Failed Whole Brain Radiation Therapy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01898130
• Other study ID #: NU 12C06
• Secondary ID: NCI-2013-00448ST
• Status: Completed
• Phase: Phase 2
• Start date: November 27, 2013
• Est. completion date: September 5, 2018

Study information

• Verified date: March 2019
• Source: Northwestern University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

PRIMARY OBJECTIVES:

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

SECONDARY OBJECTIVES:

I. 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.

III. 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 27
• Est. completion date: September 5, 2018
• Est. primary completion date: March 23, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Metastatic Cancer
• Neoplasm Metastasis
• Unspecified Adult Solid Tumor, Protocol Specific

Intervention

Biological:
• bevacizumab
Given IV

Procedure:
• quality-of-life assessment
Ancillary studies

Locations

Country	Name	City	State
United States	Northwestern University	Chicago	Illinois
United States	Northwestern Memorial Hospital: Lake Forest Hospital	Lake Forest	Illinois
United States	Columbia University Medical Center	New York	New York
United States	Cadence Health - CDH	Warrenville	Illinois

Sponsors (2)

Lead Sponsor	Collaborator
Northwestern University	Genentech, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Objective Radiographic Tumor Response in Patients With Recurrent Solid Tumor Brain Metastases Treated With Bevacizumab	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.	Every other cycle, starting cycle 3 (1 cycle =28 days) until off study. Range of cycles completed 1-20.
Secondary	Progression-Free Survival (PFS) at 6 Months in Patients With Recurrent Solid Tumor Brain Metastases Treated With Bevacizumab	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.	At 6 months from treatment initiation.
Secondary	Time to Progression in Patients With Recurrent Solid Tumor Brain Metastases Treated With Bevacizumab	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.	From treatment initiation, every 2 cycles (1 cycle = 28 days) until progressive disease. Range of cycles completed 1-20.
Secondary	Time to Response in Patients With Recurrent Solid Tumor Brain Metastases Treated With Bevacizumab	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.	From the start of treatment every 2 cycles (1 cycle =28 days) until time of response. Range of cycles completed 1-20.
Secondary	Duration of Response in Patients With Recurrent Solid Tumor Brain Metastases Treated With Bevacizumab	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.	From documentation of response, every two cycles (1 cycle =28 days) until progressive disease. Range of cycles completed 1-20.
Secondary	Overall Survival (OS) in Patients With Recurrent Solid Tumor Brain Metastases Treated With Bevacizumab	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.	From start of treatment until death from any cause. Median follow up of 8 months (range 1.3 to 47.9 months)
Secondary	Toxicity of Bevacizumab in Patients With Recurrent Solid Tumor Brain Metastases	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.	Assessed prior to every cylcle (cycle=28 days) while on treatment through 30 days post last dose. Range of cycles 1-20.
Secondary	Quality of Life Assessments in Patients With Recurrent Solid Tumor Brain Metastases Treated With Bevacizumab	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)	Baseline and at Cycle 3 (1 Cycle = 28 days).