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

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ClinicalTrials.gov Identifier: NCT02490878
Recruitment Status : Terminated (Slow accrual)
First Posted : July 7, 2015
Results First Posted : August 6, 2021
Last Update Posted : August 6, 2021
Sponsor:
Collaborators:
National Cancer Institute (NCI)
Genentech, Inc.
Information provided by (Responsible Party):
Alliance for Clinical Trials in Oncology

Tracking Information
First Submitted Date  ICMJE July 2, 2015
First Posted Date  ICMJE July 7, 2015
Results First Submitted Date  ICMJE April 24, 2020
Results First Posted Date  ICMJE August 6, 2021
Last Update Posted Date August 6, 2021
Actual Study Start Date  ICMJE April 2016
Actual Primary Completion Date February 1, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 15, 2021)
Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score [ Time Frame: Baseline, 2, 4, 6 and 8 weeks ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: July 6, 2015)
Patient-reported outcome (symptoms) of radionecrosis [ Time Frame: Up to 8 weeks ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 15, 2021)
  • Toxicity (CTCAE Version 4.0) [ Time Frame: Up to 1.5 years post-treatment ]
    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.
  • Quality of Life Measure Using the Single Item Linear Analogue Scale (LASA) [ Time Frame: Up to 1.5 years post-treatment ]
    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.
  • Quality of Life Measure Using the Dexamethasone Symptoms Questionnaire - Chronic (DSQ-C) [ Time Frame: Baseline and weeks 2, 4, 6, 8 of treatment ]
    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.
  • Quality of Life Measure Using the The M. D. Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) Score. [ Time Frame: Up to 1.5 years post-treatment ]
    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.
  • Progression Free Survival [ Time Frame: Up to 16 weeks ]
    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.
  • Time to Maximum Radiographic Response [ Time Frame: Up to 16 weeks ]
    Time from start of treatment to maximum radiographic response
  • Time to Stopping Corticosteroids [ Time Frame: Up to 16 weeks ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: July 6, 2015)
  • Toxicities associated with bevacizumab and corticosteroids in patients with radionecrosis using CTCAE Version 4.0 and DSQ-C. [ Time Frame: Up to 1.5 years post-treatment ]
  • Quality of Life Measure Using the Single Item Linear Analogue Scale (LASA) [ Time Frame: Up to 1.5 years post-treatment ]
  • Quality of Life Measure Using the Dexamethasone Symptoms Questionnaire - Chronic (DSQ-C) [ Time Frame: Up to 1.5 years post-treatment ]
  • Quality of Life Measure Using the The M. D. Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) Score. [ Time Frame: Up to 1.5 years post-treatment ]
  • Progression Free Survival [ Time Frame: Up to 16 weeks ]
  • Corticosteroid dose over time [ Time Frame: Up to 16 weeks ]
  • Maximum radiographic response [ Time Frame: Up to 16 weeks ]
  • Time to Stopping Corticosteroids [ Time Frame: Up to 16 weeks ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Corticosteroids + Bevacizumab vs. Corticosteroids + Placebo (BEST) for Radionecrosis After Radiosurgery for Brain Metastases
Official Title  ICMJE Randomized Phase II Study: Corticosteroids + Bevacizumab vs. Corticosteroids + Placebo (BEST) for Radionecrosis After Radiosurgery for Brain Metastases
Brief Summary 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

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:

  1. To evaluate the toxicity profile associated with bevacizumab and corticosteroid therapy.
  2. 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.
  3. To compare intracranial progression-free survival and time to maximum radiographic response between treatment arms.
  4. 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Supportive Care
Condition  ICMJE
  • Radionecrosis
  • Brain Metastases
Intervention  ICMJE
  • Drug: bevacizumab
    IV
  • Drug: corticosteroids
    IV
  • Other: placebo
    IV
Study Arms  ICMJE
  • Experimental: bevacizumab + corticosteroids

    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.

    Interventions:
    • Drug: bevacizumab
    • Drug: corticosteroids
  • Experimental: placebo + corticosteroids

    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.

    Interventions:
    • Drug: corticosteroids
    • Other: placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: July 15, 2021)
19
Original Estimated Enrollment  ICMJE
 (submitted: July 6, 2015)
130
Actual Study Completion Date  ICMJE April 25, 2020
Actual Primary Completion Date February 1, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Pre-Registration Eligibility Criteria:

  1. 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
  2. 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)
  3. 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:

  1. 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.

  2. 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.

  3. 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.
  4. Age ≥ 18 years
  5. Karnofsky Performance Status ≥ 60%
  6. 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

  7. 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.

  8. 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.
  9. 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.

  10. 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.

  11. No history of bowel obstruction, abdominal fistula, gastrointestinal perforation, or intra- abdominal abscess within past 12 months.
  12. No central lung metastases with excessive active bleeding.
  13. 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.

  14. No history of serious non-healing wound, ulcer, or bone fractures.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02490878
Other Study ID Numbers  ICMJE A221208
NCI-2015-01348 ( Registry Identifier: NCI Clinical Trials Reporting Program )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Alliance for Clinical Trials in Oncology
Study Sponsor  ICMJE Alliance for Clinical Trials in Oncology
Collaborators  ICMJE
  • National Cancer Institute (NCI)
  • Genentech, Inc.
Investigators  ICMJE
Study Chair: Caroline Chung, MD M.D. Anderson Cancer Center
PRS Account Alliance for Clinical Trials in Oncology
Verification Date July 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP