Corticosteroids + Bevacizumab vs. Corticosteroids + Placebo (BEST) for Radionecrosis After Radiosurgery for Brain Metastases

Study Overview
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Brief Summary
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This randomized phase II study aims to investigate whether the addition of bevacizumab to standard corticosteroid therapy results in greater improvement in symptoms and less treatment-induced symptoms compared with standard corticosteroid therapy for patients with symptomatic brain radionecrosis following radiosurgery. It is hypothesized that the addition of bevacizumab to standard care corticosteroids will reduce treatment-induced toxicities and improve neurologic impairments in patients with brain radionecrosis following radiosurgery for brain metastases.

Detailed Description
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This is a randomized double-blinded phase II study of corticosteroids with bevacizumab vs. corticosteroids with placebo for brain radionecrosis following radiosurgery for brain metastases. This is a two-arm clinical trial with parallel group design for longitudinal quality of life endpoint. Patients will be stratified according to age (≤ 65 years vs. > 65 years), pathological confirmation of necrosis (yes vs. no), MDASI-BT mean global score (symptom + interference scores) ( < 4.0 vs. > 4.0) and prior whole brain radiotherapy (yes vs. no). The primary and secondary objectives are detailed below. Primary Objective: To investigate whether the addition of bevacizumab to standard corticosteroid therapy results in greater improvement in symptoms (clinical and patient-reported symptom improvement associated with radionecrosis and less radionecrosis treatment-induced symptoms) compared with standard corticosteroid therapy. Secondary Objectives: To evaluate the toxicity profile associated with bevacizumab and corticosteroid therapy. To compare self-reported health related quality of life (HRQOL) using LASA, Dexamethasone Symptoms Questionnaire-Chronic (DSQ-C), and MDASI-BT symptom and interference score between treatment arms. To compare intracranial progression-free survival and time to maximum radiographic response between treatment arms. To compare the dose and duration of corticosteroids required between treatment arms and correlate steroid requirement with DSQ-C and MDASI-BT scores. Patient event monitoring will occur every 2 months after treatment up to 6 months. Then event monitoring will occur up to one year.

Official Title
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Randomized Phase II Study: Corticosteroids + Bevacizumab vs. Corticosteroids + Placebo (BEST) for Radionecrosis After Radiosurgery for Brain Metastases

Conditions
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Radionecrosis, Brain Metastases

Intervention / Treatment
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* Drug: bevacizumab
* Drug: corticosteroids
* Other: placebo


Participation Criteria
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Eligibility Criteria
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Pre-Registration Eligibility Criteria: Patients who present with symptomatic brain radionecrosis after they have received radiosurgery for brain metastases from primary solid tumor including but not limited to lung, breast, colorectal cancer but excluding melanoma, choriocarcinoma, renal cell carcinoma or gliomas Patients at institutions that elect to utilize central imaging review to confirm eligibility must be pre-registered prior to submission of these images; images should be submitted as soon as possible after the pre-registration magnetic resonance imaging (MRI) is obtained; turnaround time for this review will be =< 72 business hours after receipt of images by the Imaging and Radiation Oncology Core (IROC) Patients at institutions that elect to confirm eligibility locally may be pre-registered at the same time as they are randomized Registration/Randomization Eligibility Criteria: A diagnosis of radionecrosis will be based on a clinical onset of symptoms and radiological findings of radionecrosis at 3-24 months following radiosurgery, with or without pathological confirmation. 1.1 'Symptomatic' brain radionecrosis to at least one lesion following radiosurgery treatment for brain metastases where 'symptomatic' is defined as: 1.1.1 New or increasing headache associated with mass effect, sensory or motor abnormality, cognitive changes, speech difficulty, balance or coordination difficulty, cranial nerve deficits 1.1.2 Symptoms are persistent or worsening despite administration of at least dexamethasone 4 mg (or equivalent corticosteroid) daily for 1 week 1.2 Clinical eligibility supported by central imaging real-time review. The presence of at least the following conventional MR image characteristic: 1.2.1 Conventional MR - Lesion quotient of < 0.3, where lesion quotient is defined as the proportional value of the maximum axial cross-sectional area of the T2-weighted defined lesion over the maximum axial cross-sectional area of the contrast-enhancing lesion on the T1-weighted post-gadolinium sequence on a comparable axial slice. If the conventional MR findings are not seen, the following dynamic susceptibility-contrast (DSC) MR characteristics may be used to meet eligibility for this study. 1.2.2 DSC MR - The cut-offs below will be based on GRE EPI DSC perfusion images, acquired without using a gadolinium pre-load: 1.2.2.1 Relative cerebral blood volume (rCBV) <1.5 in the enhancing- lesion relative to normal-appearing white matter (NAWM) 1.2.2.2. Percentage of signal recovery (PSR) > 76%, where PSR is determined by comparing the lower signal intensity during passage of the contrast bolus with the post-contrast signal intensity on the signal intensity-time curve 1.2.3 Centers that standardly use PET or MRS to determine a diagnosis of radionecrosis are permitted to use these modalities to assist in their patient selection; however the criteria described for conventional MR and/or DSC should also be met for study eligibility. Both PET and MRS are not mandatory for study eligibility. Prior to start of treatment 2.1 Must have been taking a stable dose of corticosteroids for symptom management for at least 1 week before baseline MRI. 2.2 No systemic therapy within 2 weeks prior to registration or plan for systemic therapy within the first 8 weeks after study registration. The protocol provides a list of 'approved systemic' therapies that are allowed for concurrent use with bevacizumab. 2.3 No bevacizumab ≤ 3 months of study registration. 2.4 Central imaging real-time review (72 hour turn around) to confirm eligibility. Not pregnant and not nursing, because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown. Therefore, for women of childbearing potential only, a negative urine or serum pregnancy test done ≤ 14 days prior to registration and confirmation they are not nursing is required. Age ≥ 18 years Karnofsky Performance Status ≥ 60% Required Initial Laboratory Values ≤14 days of registration: 6.1 Absolute Neutrophil Count (ANC) ≥ 1,500/mm^3 6.2 Platelet Count ≥ 100,000/mm3 6.3 Hemoglobin ≥ 10 g/dL* 6.3.1 allowing transfusion or other intervention to achieve this minimum hemoglobin 6.4 BUN < 30 mg/dL 6.5 Creatinine < 1.7 mg/dL 6.6 Bilirubin ≤ 2.0 mg/dL 6.7 ALT ≤ 3.0 x upper limits of normal (ULN) 6.8 AST ≤ 3.0 x ULN 6.9 INR <1.5 x ULN** 6.9.1 unless patients are receiving anti-coagulation therapy. Patients receiving anti-coagulation therapy with an agent such warfarin or heparin are allowed to participate if INR ≤ 3.0.** 6.10 UPC Ratio <0.5 or if ≥ 0.5 6.10.1 24-hour urine protein must be <1000 mg Able to participate in patient-report outcomes (MDASI-BT, DSQ-C, LASA) questionnaires. Assistance by research personnel is acceptable if participant has disabilities that make reading or writing difficult. No evidence of recent hemorrhage at pre-registration MRI of the brain, however the following are permitted: presence of hemosiderin, resolving hemorrhagic changes related to surgery, and presence of punctate hemorrhage in the tumor. No excess risk of bleeding (any of the following): 9.1 Bleeding diathesis or coagulopathy 9.2 Thrombocytopenia 9.3 Major surgical procedure, open biopsy, or significant traumatic injury within the past 28 days or anticipation of need for major surgical procedure during the course of the study. 9.4 Minor surgical procedures, stereotactic biopsy, fine needle aspiration, or core biopsy within the past 7 days. No clinically significant cardiovascular disease. 10.1 No uncontrolled hypertension (systolic blood pressure ≤ 160 mm Hg or diastolic ≤ 100 mm Hg). Patients with hypertension must be adequately controlled with appropriate anti-hypertensive therapy or diet. 10.2 No history of arterial thrombotic events within the past 6 months, including: 10.2.1 transient ischemic attack (TIA) 10.2.2 cerebrovascular accident (CVA) 10.2.3 peripheral arterial thrombus 10.2.4 unstable angina or angina requiring surgical or medial intervention 10.2.5 myocardial infarction (MI) 10.2.6 significant peripheral artery disease (i.e., claudication on less than one block) 10.2.7 significant vascular disease (i.e., aortic aneurysm, history of aortic dissection) 10.3 Patients who have had a deep vein thrombosis or pulmonary embolus within the past 6 months are eligible if they are on stable therapeutic anticoagulation. 10.4 No current New York Heart Association classification II, III, or IV congestive heart failure. No history of bowel obstruction, abdominal fistula, gastrointestinal perforation, or intra- abdominal abscess within past 12 months. No central lung metastases with excessive active bleeding. No uncontrolled intercurrent illness including, but not limited to any of the following: ongoing or active infection requiring IV antibiotics, cardiac arrhythmia, or psychiatric illness and/or social situations that would limit compliance with study requirements. No history of serious non-healing wound, ulcer, or bone fractures.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: bevacizumab + corticosteroids<br>The patient will receive bevacizumab 10 mg/kg IV given on days 1 and 15 of a 28 day cycle for 4 cycles. Once the patient has started the study treatment, the dose of corticosteroids will be tapered every 5 days (e.g., dexamethasone 2 mg or prednisone 15 mg per taper), as tolerated, under the management of the treating MD. If patients deteriorate while tapering, dexamethasone will be increased up to a maximum of 16 mg per day, as per treating MD, to manage symptoms. Patients who meet the criteria for clinical progression will be treated as per treating MD. | Drug: bevacizumab<br>* IV<br>Drug: corticosteroids<br>* IV<br>|
| Experimental: placebo + corticosteroids<br>The patient will receive placebo 0.9% NaCl volume equal to bevacizumab volume added to 100 mL bag of 0.9% NaCl delivered IV given on days 1 and 15 of a 28-day cycle for 4 cycles. Once the patient has started the study treatment, the dose of corticosteroids will be tapered every 5 days (e.g., dexamethasone 2 mg or prednisone 15 mg per taper), as tolerated, under the management of the treating MD. If patients deteriorate while tapering, dexamethasone will be increased up to a maximum of 16 mg per day, as per treating MD, to manage symptoms. Patients who meet the criteria for clinical progression will be allowed to receive bevacizumab according to the protocol. | Drug: corticosteroids<br>* IV<br>Other: placebo<br>* IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score | The MD Anderson Symptom Inventory for brain tumor (MDASI-BT) is a 28-item multi-symptom patient-reported outcome measure assessing the severity of symptoms experienced by cancer patients and the interference with daily living caused by these symptoms, with 9 items specific to brain tumors. Each item ranges from 0 (best condition) to 10 (worst condition). A subscale score (Symptom Severity) is the average of the subscale items with 0 being not present and 10 being as bad as you can imagine., given that a specified minimum numbers of items were completed. A negative change in score from baseline to given time point indicates a worsening score. | Baseline, 2, 4, 6 and 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity (CTCAE Version 4.0) | Toxicity associated with bevacizumab and corticosteroids in patients with radionecrosis using CTCAE Version 4.0. The number of patients reporting a grade 3 or higher, 4 or higher, or 5 at least possibly related to treatment are included in this table. | Up to 1.5 years post-treatment | 
| Quality of Life Measure Using the Single Item Linear Analogue Scale (LASA) | The Linear Analogue Scale used is a 5-question survey. Patients are asked to score the following questions on a 1(as bad as it can be) -10 (as good as it can be) scale: 1) your overall quality of life, 2) your overall (intellectual) well being, 3) your overall physical well being, 4) your overall emotional well being, and 5) your overall spiritual well being. The change in score was computed from baseline to 1.5 years post-treatment. A negative difference is thought of as a worsening score from baseline. | Up to 1.5 years post-treatment | 
| Quality of Life Measure Using the Dexamethasone Symptoms Questionnaire - Chronic (DSQ-C) | The DSQ-C was developed for use in the brain tumor patient population. It consists of 18 questions rated on a 4-point scale (1 to 4, with 4 indicating a worse symptom) to indicate the presence and severity of symptoms. For each patient, the sum across all 18 questions were computed(18-72, with 18 being a score of 1 for each of the 18 questions and 72 being a score of 4 for each of the questions, refering to the previous sentence, a score of 18(a score of 1, 18 times) indicates the best possible score. A score of 72(a score of 4, 18 times) indicates the worst possible. The mean for total score across each week (weeks 2, 4, 6, 8) is reported. | Baseline and weeks 2, 4, 6, 8 of treatment | 
| Quality of Life Measure Using the The M. D. Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) Score. | The MDASI-BT was developed and validated for use in the brain tumor patient population, including those with brain metastases and typically requires less than 4 minutes to complete. It consists of 23 symptoms rated on a 0 to 10 numerical rating scale (NRS) to indicate the presence and severity of the symptom, with 0 being not present and 10 being as bad as you can imagine. MDASI-BT Symptom Scoring: A global symptom score for the MDASI symptom severity scale is obtained by taking the average of the 23 items together. This puts the score on a 0-10 scalenumerical rating scale (NRS) to indicate the presence and severity of the symptom, with 0 being not present and 10 being as bad as you can imagine. The mean global symptom at baseline and at weeks 2, 4, 6, 8 were used in this analysis. | Up to 1.5 years post-treatment | 
| Progression Free Survival | Progression free survival is defined as the time from start of treatment to the earliest of the date patient stops placebo or bevacizumab for either alternative therapy or crossover to bevacizumab (if initially on placebo). Result will be summarized by Kaplan-Meier method. | Up to 16 weeks | 
| Time to Maximum Radiographic Response | Time from start of treatment to maximum radiographic response | Up to 16 weeks | 
| Time to Stopping Corticosteroids | Time to stopping corticosteroids is defined as the time from start of protocol treatment to the last day corticosteroids were given. Time to stopping corticosteroid will be summarized by Kaplan-Meier curve with log-rank tests conducted to investigate differences between treatment arms. | Up to 16 weeks |