Clinical Trials /

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

NCT02490878

Description:

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.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: A221208
  • SECONDARY ID: NCI-2015-01348
  • NCT ID: NCT02490878
  • NCT ALIAS: NCT02531659

Conditions

  • Radionecrosis
  • Brain Metastases

Interventions

DrugSynonymsArms
bevacizumabbevacizumab + corticosteroids
corticosteroidsbevacizumab + corticosteroids

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
bevacizumab + corticosteroidsExperimentalThe 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.
  • bevacizumab
  • corticosteroids
placebo + corticosteroidsExperimentalThe 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.
  • corticosteroids

Eligibility Criteria

        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 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 need 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Patient-reported outcome (symptoms) of radionecrosis
Time Frame:Up to 8 weeks
Safety Issue:
Description:

Secondary Outcome Measures

Measure: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
Safety Issue:
Description:
Measure:Quality of life measure using the Single Item Linear Analogue Scale (LASA)
Time Frame:Up to 1.5 years post-treatment
Safety Issue:
Description:
Measure:Quality of life measure using the Dexamethasone Symptoms Questionnaire - Chronic (DSQ-C)
Time Frame:Up to 1.5 years post-treatment
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure:Progression free survival
Time Frame:Up to 16 weeks
Safety Issue:
Description:
Measure:Corticosteroid dose over time
Time Frame:Up to 16 weeks
Safety Issue:
Description:
Measure:Maximum radiographic response
Time Frame:Up to 16 weeks
Safety Issue:
Description:
Measure:Time to stopping corticosteroids
Time Frame:Up to 16 weeks
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Alliance for Clinical Trials in Oncology

Last Updated

August 15, 2017