Border Zone Stereotactic Radiosurgery With Bevacizumab in Patients With Glioblastoma Multiforme

Phase 2

Completed

• Conditions: Glioblastoma Multiforme; Glioblastoma - Category
• Interventions: Drug: Bevacizumab; Procedure: Magnetic Resonance Spectroscopy (MRS); Procedure: Border Zone Stereotactic Radiosurgery (BZ-SRS)

• Registration Number: NCT02120287
• Lead Sponsor: Ajay Niranjan

Brief Summary

This is a phase II study on the usage of stereotactic Gamma Knife radiosurgery as a boost to the tumor bed border zone in conjunction with the usage of bevacizumab.

Detailed Description

Glioblastoma Multiforme (GBM) is the most common primary brain tumor in adults. Unfortunately, despite aggressive surgery, radiation therapy (RT) and chemotherapy, the prognosis for this disease is poor. It is our hypothesis that GBM is a "local" disease wherein treatment failure is due to failure to eradicate tumor cells in the pathways along which the tumor eventually spreads (the "border zone").

The investigators hypothesize that treatment volume escalation will be successful at improving overall survival in patients with GBM when appropriate targeting and precision dose delivery is performed in a single treatment session. The 'border zone' of the tumor will be targeted for SRS (defined as a combination of the MRI volume of gadolinium enhancement plus up to 2 cm of the surrounding T2 volume). This represents the volume of tumor infiltrated white matter and is the route of GBM spread. Bevacizumab, a monoclonal antibody to vascular endothelial growth factor (VEGF), has been used with safety and clinical success with concomitant chemotherapy in solid tumors, including GBM.

The investigators further hypothesize that a combined approach of SRS with this VEGF inhibitor will be an effective strategy for GBM because bevacizumab will maximize the effects of radiation in the treated volume and potentially reduce radiation toxicity in the adjacent brain.

Study Timeline

• Study First Submitted: 2014-01-10
• Study First Submitted QC: 2014-04-18
• Study First Posted: 2014-04-22
• Study Start: 2014-05
• Primary Completion: 2018-03-31
• Study Completion: 2018-03-31
• Status Verified: 2019-04
• Results First Submitted: 2019-04-02
• Results First Submitted QC: 2019-04-02
• Results First Posted: 2019-04-25
• Last Update Submitted: 2019-04-25
• Last Update Posted: 2019-05-07

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 16

Inclusion Criteria

1. Histologically confirmed glioblastoma multiforme, WHO grade IV astrocytoma.
2. Prior first-line treatment with surgery or biopsy followed by fractionated radiotherapy with concurrent temozolomide-containing chemotherapy is required for glioblastoma patients. Additional prior chemotherapy is allowed, without limitation on number of recurrences.
3. An interval of at least 2 months since completion of fractionated radiotherapy.
4. Age > 18 years
5. Life expectancy of at least 12 weeks.
6. Karnofsky Performance Status score (KPS) of ≥ 60
7. Documented recurrent disease; Disease must be evaluable, but does not need to be measurable; the target site for SRS does not need to be located in a previously-irradiated area.
8. All patients must have no restrictions to obtaining MRI with and without gadolinium contrast.
9. Adequate bone marrow, hepatic and renal function ; BUN < 25 and Cr < 1.7
10. Negative pregnancy test at the time of SRS in any patient who could be pregnant.
11. Willingness to forego additional therapy until evidence of disease progression

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Exclusion Criteria

1. General Medical Exclusions:

2. Current, recent (within 4 weeks of the first infusion of this study), or planned participation in an experimental drug study.

3. Active malignancy, other than superficial basal cell and superficial squamous (skin) cell, or carcinoma in situ of the cervix within last 3 years.

4. Prior radiosurgery

5. Prior intracavitary irradiation or Gliadel wafers.

6. Disease-Specific Exclusions:

7. Inability to comply with protocol or study procedures

8. Prior treatment with bevacizumab.

9. Inability to undergo MRI with and without contrast administration.

10. Bevacizumab-Specific Exclusions:

11. Inadequately controlled hypertension.

12. Prior history of hypertensive crisis or hypertensive encephalopathy.

13. New York Heart Association (NYHA) Grade II or greater congestive heart failure.

14. History of myocardial infarction or unstable angina within 6 months prior to Day 1.

15. History of stroke or transient ischemic attack within 6 months prior to Day 1.

16. Significant vascular disease within 6 months prior to Day 1.

17. History of hemoptysis within 1 month prior to Day 1.

18. Evidence of bleeding diathesis or significant coagulopathy

19. Major surgical procedure, open biopsy, or significant traumatic injury within 14 days prior to Day 1 or anticipation of need for major non -cranial surgical procedure during the course of the study.

20. Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to Day 1.

21. History of abdominal fistula or gastrointestinal perforation within 6 months prior to Day 1.

22. Serious, non-healing wound, active ulcer, or untreated bone fracture.

23. Proteinuria

24. Known hypersensitivity to any component of bevacizumab

25. Pregnancy (positive pregnancy test) or lactation. Use of effective means of contraception (men and women) in subjects of child-bearing potential.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
BZ-SRS with Bevacizumab	Magnetic Resonance Spectroscopy (MRS)	All patients will receive Border Zone Stereotactic Radiosurgery (BZ-SRS) and additionally receive bevacizumab (10 mg/kg) one day before and then at day 14 followed by 10 mg/kg/day every 14 days until progression. One to 14 days before BZ- SRS procedure, patients at centers with MRS experience will undergo standard brain MRI /MRS
BZ-SRS with Bevacizumab	Border Zone Stereotactic Radiosurgery (BZ-SRS)	All patients will receive Border Zone Stereotactic Radiosurgery (BZ-SRS) and additionally receive bevacizumab (10 mg/kg) one day before and then at day 14 followed by 10 mg/kg/day every 14 days until progression. One to 14 days before BZ- SRS procedure, patients at centers with MRS experience will undergo standard brain MRI /MRS
BZ-SRS with Bevacizumab	Bevacizumab	All patients will receive Border Zone Stereotactic Radiosurgery (BZ-SRS) and additionally receive bevacizumab (10 mg/kg) one day before and then at day 14 followed by 10 mg/kg/day every 14 days until progression. One to 14 days before BZ- SRS procedure, patients at centers with MRS experience will undergo standard brain MRI /MRS

Primary Outcome Measures

Name	Time	Method
Overall Survival (OS)	Up to 2 years	The number of months that a patient remains alive from the day first gamma knife surgery until the date of death or end of data collection for survival.

Secondary Outcome Measures

Name	Time	Method
Center for Epidemiological Studies Depression Scale (CES-D)	At 8 weeks	An assessment comprised of 20 statements for which the participant is asked to indicate how often they have felt a certain way during the past week. SCORING: zero for answers of Rarely or none of the time (less than 1 day), 1 for answers of Some or a little of the time (1-2 days), 2 for answers of Occasionally or a moderate amount of time (3-4 days) the third column, 3 for answers of Most or all of the time (5-7 days). The scoring of positive items is reversed. Possible range of scores is zero to 60, with the higher scores indicating the presence of more depression symptomatology.
CNS Toxicity	Six months after SRS	The number of patients experiencing a CNS toxicity type occurring within 3 months of gamma knife surgery, as measured by RTOG/EORTC Acute Radiation Morbidity Scoring and the NCI CTCAE v4.0 for late toxicity.
6-month Progression-free Survival	At 6 months	The proportion of patients who did not experience disease progression per RANO as of 6 months from the date of radiosurgery. RANO (Response Assessment in Neuro-Oncology) Response Criteria for Progression using imaging features: 25% or more increase in enhancing lesions despite stable or increasing steroid dose increase (significant) in non-enhancing FLAIR/T2W lesions, not attributable to other non-tumor causes any new lesions clinical features clinical deterioration (not attributable to other non-tumor causes and not due to steroid decrease). Proportion of patients for PFS = number of patients without disease at 6 months post radiosurgery / total number of patients.
6-month Overall Survival	At 6 months	The proportion of patients who remained alive as of 6 months from the date of radiosurgery. Proportion of patients for OS = number of patients alive at 6 months post radiosurgery / total number of patients.
Tumor Response	Up to 2 years	Proportion of patients with a best response of CR, PR, SD, PD: number of patients with CR, PR, SD or PD / total number of patients evaluable for response to treatment of border zone Stereotactic Radiosurgery (BZ-SRS) with bevacizumab.
Barthel's Index of Activities of Daily Living Assessment	At 8 weeks	The Barthel Index consists items assessing the ability to achieve certain activities without assistance. It evaluates the ability of feeding, moving from wheelchair to bed and returning, doing personal toilet, getting on and off toilet,bathing self, walking on level surface, ascending and descending stairs, dressing, controlling bowels and controlling bladder. Scoring ranged from 0 (completely dependent) to 20 (completely independent) for this assessment. A maximal score of 20 indicating that a patient is fully independent in physical functioning, and a lowest score of 0 representing a totally dependent bed-ridden state.
Functional Assessment of Cancer Therapy-Brain Specific Symptom Index (FACT-BrSI)	At 8 weeks	The FACT-BrSI subscale, brain tumor specific version (2007), is a 15-item, patient completed, questionnaire.This brain subscale is used along with the core (general) questionnaire (FACT-G) that includes 27 items. Patients rate all items using a five-point Likert scale ranging from 0 "not at all" to 4 "very much." Overall, higher ratings suggest higher quality of life (QOL). The FACT BrSI has a range of 0-60, where a higher score indicates less symptomatology.
Karnofsky Performance Status	At baseline (Week 0) prior to treatment administration	The Karnofsky Performance Scale Index allows patients to be classified as to their functional impairment. This can be used to compare effectiveness of different therapies and to assess the prognosis in individual patients. Score range from 0 to 100; the lower the Karnofsky score, the worse the survival for most serious illnesses. A score of 100 would indicate 'Normal no complaints; no evidence of disease.' A score of 50 indicates 'Requires considerable assistance and frequent medical care.' A score of 0-10 would indicate 'Moribund; fatal processes progressing rapidly' and 'Death'.
Functional Assessment of Cancer - General (FACT-G)	At baseline (Week 0) prior to treatment administration	The FACT-G is a patient rated, 27-item compilation of general questions divided into 4 primary Quality of Life (QOL) sub-scales: physical well-being (PWB; 7-items, score range 0-28), social/family well-being (SWB; 7-items, score range 0-28), emotional well-being (EWB; 6-items, score range 0-24), and functional well-being (FWB; 7-items, score range 0-28). This tool represents the generic core questionnaire that are utilized in combination with cancer site-specific questionnaires, (FBrain, in this study) Overall score and four subscale scores with ranges and distributions that are sample-specific can be calculated.FACT-G is scored by summing the individual scale scores; higher scores indicate better quality of life. FACT-G uses 5-point rating scale ranging from (0) = Not at all; (1) = A little bit; (2) = Somewhat; (3) = Quite a bit; to (4) = Very much.The FACT-G total score is the sum of the four subscale scores (if least 80% completed) and has a possible range of 0-108 points.
Potential Value of Magnetic Resonance Spectroscopy (MRS)	Prior to radiosurgery	Improvement of border zone target selection and detection of therapeutic response of the derived treatment volumes between MRI and MRI+MRS (Magnetic Resonance Spectroscopy).; This is presented as the number of patients for whom the derived treatment was changed as a result of the utilization of MRS.
Functional Assessment of Cancer Therapy-General - General (FACT-G)	At 8 weeks	The FACT-G is a patient rated, 27-item compilation of general questions divided into 4 primary Quality of Life (QOL) sub-scales: physical well-being (PWB; 7-items, score range 0-28), social/family well-being (SWB; 7-items, score range 0-28), emotional well-being (EWB; 6-items, score range 0-24), and functional well-being (FWB; 7-items, score range 0-28). This tool represents the generic core questionnaire that are utilized in combination with cancer site-specific questionnaires, (FBrain, in this study) Overall score and four subscale scores with ranges and distributions that are sample-specific can be calculated.FACT-G is scored by summing the individual scale scores; higher scores indicate better quality of life. FACT-G uses 5-point rating scale ranging from (0) = Not at all; (1) = A little bit; (2) = Somewhat; (3) = Quite a bit; to (4) = Very much.The FACT-G total score is the sum of the four subscale scores (if least 80% completed) and has a possible range of 0-108 points.

Trial Locations

Locations (1)

University of Pittsburgh; 🇺🇸 Pittsburgh, Pennsylvania, United States