Efficacy of Hypofractionated XRT w/Bev. + Temozolomide for Recurrent Gliomas

• Sponsor: Northwestern University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01478321
• Collaborator: (none)
• Enrollment: 54
• Locations: 5
• Arm: 1
• Actual Duration (Months): 81
• Patients Per Site: 10.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This phase II trial studies how well giving hypofractionated radiation therapy together with temozolomide and bevacizumab works in treating patients with high-grade glioblastoma multiforme or anaplastic glioma. Specialized radiation therapy, such as hypofractionated radiation therapy, that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Giving hypofractionated radiation therapy together with temozolomide and bevacizumab may kill more tumor cells.

Condition or Disease	Intervention/Treatment	Phase
Adult Anaplastic Astrocytoma; Adult Anaplastic Ependymoma; Adult Anaplastic Oligodendroglioma; Adult Giant Cell Glioblastoma; Adult Glioblastoma	Drug: Temozolomide; Radiation: hypofractionated radiation therapy; Biological: bevacizumab; Other: questionnaire administration	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To determine the overall survival (OS) for patients with recurrent high grade malignant gliomas treated with concurrent radiation, temozolomide, and bevacizumab followed by adjuvant temozolomide and bevacizumab.

SECONDARY OBJECTIVES:

1. Determine the impact of this regimen on neurologic symptoms via Functional Assessment of Cancer Therapy-Brain (FACT-Br) and FACT-Fatigue scales and Eastern Cooperative Oncology Group (ECOG) performance status.

2. Determine the safety profile of this regimen. III. Determine the progression free survival (PFS) at 6 and 12 months (all patients) as well as at 3 months (bevacizumab-exposed patients only).

OUTLINE:

CONCURRENT THERAPY: Patients undergo hypofractionated radiation therapy 5 days a week beginning on day 0. Patients also receive temozolomide orally (PO) once daily (QD) and bevacizumab intravenously (IV) over 30-90 minutes once every 2 weeks beginning on days -3 to 0. Treatment continues for 5 weeks in the absence of disease progression or unacceptable toxicity.

ADJUVANT THERAPY: Beginning 2 weeks after completion of radiation therapy, patients receive temozolomide PO QD for 6 weeks and bevacizumab IV over 30-90 minutes once every 2 weeks. Courses repeat every 8 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 2-3 months.

Study Design

• Study Type: Interventional
• Actual Enrollment: 54 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of the Efficacy of Hypofractionated Radiation Therapy With Bevacizumab and Temozolomide Followed by Maintenance Temozolomide and Bevacizumab for Recurrent High-Grade Gliomas
• Actual Study Start Date: Dec 14, 2011
• Actual Primary Completion Date: Sep 12, 2018
• Actual Study Completion Date: Sep 12, 2018

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (radiation, chemotherapy, monoclonal antibody) CONCURRENT THERAPY: Patients undergo hypofractionated radiation therapy 5 days a week beginning on day 0. Patients also receive temozolomide PO QD and bevacizumab IV over 30-90 minutes once every 2 weeks beginning on days -3 to 0. Treatment continues for 5 weeks in the absence of disease progression or unacceptable toxicity. ADJUVANT THERAPY: Beginning 2 weeks after completion of radiation therapy, patients receive temozolomide PO QD for 6 weeks and bevacizumab IV over 30-90 minutes once every 2 weeks. Courses repeat every 8 weeks in the absence of disease progression or unacceptable toxicity.

Drug: Temozolomide; Given PO; Other Names: TMZ ; Radiation: hypofractionated radiation therapy; Undergo hypofractionated radiation therapy; Biological: bevacizumab; Given IV; Other Names: anti-VEGF humanized monoclonal antibody, ; Other: questionnaire administration; Ancillary studies

Outcome Measures

Primary Outcome Measures

1. Overall Survival (OS) for Patients With Recurrent High Grade Malignant Gliomas Treated With Concurrent Radiation, Temozolomide, and Bevacizumab Followed by Adjuvant Temozolomide and Bevacizumab. [From treatment initiation and every 8 weeks for up to 53.5 months]

   Data will be analyzed using Kaplan-Meier curves. OS is defined as the time from first re-irradiation treatment until death from any cause.

Secondary Outcome Measures

1. Patient Reported Quality of Life (QOL) [Completed before treatment (baseline) after Cycle 1 (approximately week 15) and Cycle 2 (approximately week 23)of adjuvant treatment and at the end of treatment (up to 7 cycles of adjuvant treatment, where 1 cycle =8 weeks)]

   Questionnaires were completed before treatment (baseline) at the end of treatment (EOT) and after Cycle 1 and Cycle 2 of treatment (Initial phase of treatment =5 weeks + approximately 2 weeks recovery then adjuvant therapy where 1 cycle = 8 weeks). The following questionnaires were completed by patients to evaluate quality of life (QOL) at these timepoints: FACT-Fatigue - scores from 1 to 4 with 1=not at all and 4=very much, the higher the score the more fatigue reported by the patient. FACT-Brain (FACT Br) which included - Physcial Well-being (PWB), Social/Family Well-being (SWB), Emotional Well-being (EWB), and Functional Well-being (FWB). Patients gave scores from 0 to 4 with 0=not at all and 4=very much, the higher the score the better the QOL reported by the patient.

2. Safety Profile for Patients With Recurrent High Grade Malignant Gliomas Treated With Concurrent Radiation, Temozolomide, and Bevacizumab Followed by Adjuvant Temozolomide and Bevacizumab [Completed weekly during initial phase of 5 weeks and 2 weeks recovery, then every cycle during adjuvant therapy where 1 cycle =8 weeks (for up to 7 cycles)]

   Toxicity will be assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 criteria on Day 1 of every treatment cycle and by patient report while on study treatment and up to 30 days after the last treatment. Grade 1 - 4 adverse events (AE) where the relationship between the AE and at least one of the study drugs were considered to be definite, probable or possible, were collected and graded as: Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE

3. Percentage of Patients With Progression Free Survival (PFS) at 6 Months and 12 Months [At 6 and 12 months after the start of treatment]

   Progression Free Survival is defined as the time from the first study treatment to the first occurrence of disease progression or death. Data will be analyzed using Kaplan-Meier curves. Tumor measurements and assessments will be based on Updated Response Assessment Criteria of High Grade Gliomas- Neuro-Oncology Working Group (RANO criteria). Tumor assessments may include either a CT or MRI scan of the brain, however the same method should be used throughout the treatment period for each patient. In general, progressive disease is defined as any of the following: ≥ 25% increase in T1 gadolinium enhancing disease, increase in T2/Flair, new lesions present or decrease in clinical status

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients must have histologically confirmed diagnosis of glioblastoma multiforme (GBM) or anaplastic glioma, World Health Organization (WHO) grade 3 or 4

• Patients must have measurable or non-measurable (evaluable) disease recurrence

• Recurrence must be documented based on a combination of clinical and imaging parameters, consistent with routine clinical practice, with or without histologic confirmation

• Patients may have had any number of relapses and be eligible for the study

• Patients must have been previously treated with radiation therapy and temozolomide (bevacizumab-naïve - Groups 1 and 3) or radiation therapy, temozolomide and bevacizumab (bevacizumab-exposed -Groups 2 and 4); therapy with these agents may be given together or sequentially in the past

• All patients may have had prior surgery, chemotherapy, and radiation therapy; prior biologic therapy is permitted only for bevacizumab-exposed patients (Groups 2 and 4); prior treatment with Gliadel is permitted for all groups

• For bevacizumab-naïve patients (Groups 1 and 3) a minimum of 6 months must have elapsed since completion of radiation therapy for study entry, and there is no minimum time since completion of last chemotherapy; for bevacizumab-exposed patients (Groups 2 and 4) no minimum time since completion of last radiation therapy, biologic agents, or chemotherapy will be required for study entry

• Patients must have an ECOG performance status of =< 2

• Hemoglobin >= 10

• Platelets >= 100,000/mm^3

• Absolute neutrophil count >= 1500/mm^3

• Bilirubin =< 1.5 x upper limit of normal range (ULN)

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN

• Blood urea nitrogen (BUN) =< 1.5 x ULN

• Creatinine =< 1.5 x ULN

• Urine protein/creatinine ratio should be =< 1

• Patients' baseline blood pressure must be adequately controlled with or without antihypertensive medications prior to enrollment (systolic < 140 mmHg, diastolic < 90 mmHg)

• Patients must have a baseline evaluation including history and physical examination with neurological evaluation and magnetic resonance imaging (MRI) of the brain (with and without gadolinium-based contrast), all completed within 30 days prior to initiation of treatment

• Female patients of child-bearing potential must have a negative pregnancy test within 14 days prior to enrollment on study; child-bearing potential is defined as any female (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets one of the following criteria:

• Has not undergone a hysterectomy or bilateral oophorectomy

• Or has not been naturally postmenopausal for at least 12 consecutive months (i.e. has had menses at any time in the preceding consecutive 12 months)

• Females of child-bearing potential and sexually-active males must consent to follow acceptable birth control methods to avoid contraception while on treatment

• All subjects must have given signed, informed consent prior to registration on study

• Patients previously treated outside of Northwestern must have their pathology slides sent to Northwestern for review and confirmation - NOTE: a copy of the pathology report is sufficient for registration

Exclusion Criteria:

• • Patients who are pregnant or breast-feeding will NOT be eligible for participation

• Patients with a prior malignancy will NOT be eligible for participation aside from the following exception:

• Patients who have had any curatively treated malignancy and have been disease free without treatment for 1 year prior to study entry ARE eligible for participation

• Patients with an active second malignancy (other than non-melanoma skin cancer or cervical cancer in situ) are NOT eligible for participation

• Patients with uncontrolled hypertension (>= 140/90 mmHg) are NOT eligible for participation

• Patients who exhibit any other serious concurrent infection or other medical illness which would jeopardize their ability to receive the therapy outlined in this protocol with reasonable safety will NOT be eligible for participation

• The eligibility criteria listed above are interpreted literally and cannot be waived

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Northwestern University	Chicago	Illinois	United States	60611
2	University of Chicago	Chicago	Illinois	United States	60637
3	Northwestern Lake Forest Hospital	Lake Forest	Illinois	United States	60045
4	Edward Cancer Center	Naperville	Illinois	United States	60540
5	Central Dupage Hospital	Warrenville	Illinois	United States	60555

Sponsors and Collaborators

• Northwestern University

Investigators

• Principal Investigator: Jeffrey Raizer, MD, Northwestern University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - May 28, 2019

More Information

Publications

None provided.

• Responsible Party: Northwestern University
• ClinicalTrials.gov Identifier: NCT01478321
• Other Study ID Numbers: NU 11C02; STU00053636; NCI CTRP#
• First Posted: Nov 23, 2011
• Last Update Posted: Mar 12, 2020
• Last Verified: Jul 1, 2019

• Keywords provided by Northwestern University: Information Not Provided
• Additional relevant MeSH terms: Glioblastoma; Astrocytoma; Ependymoma; Oligodendroglioma; Bevacizumab; Temozolomide

Study Results

Participant Flow

Recruitment Details	The study opened for accrual on November 14, 2011 with an accrual goal of up to 77 patients and the first patient being enrolled on December 14, 2011. The study was closed permanently on March 24, 2017 due to low accrual with 54 patients treated on the study.

Arm/Group Title	Treatment (Radiation, Chemotherapy, Monoclonal Antibody)
Arm/Group Description	CONCURRENT THERAPY: Patients undergo hypofractionated radiation therapy 5 days a week beginning on Day 0. Patients also receive temozolomide PO QD and bevacizumab IV over 30-90 minutes once every 2 weeks beginning on Days -3 to 0. Treatment continues for 5 weeks in the absence of disease progression or unacceptable toxicity. ADJUVANT THERAPY: Beginning 2 weeks after completion of radiation therapy, patients receive temozolomide PO QD for 6 weeks and bevacizumab IV over 30-90 minutes once every 2 weeks. Courses repeat every 8 weeks in the absence of disease progression or unacceptable toxicity. Temozolomide: Given PO Hypofractionated Radiation Therapy: Undergo hypofractionated radiation therapy Bevacizumab: Given IV Questionnaire administration: Ancillary studies
Period Title: Concurrent Therapy (5 Weeks)
STARTED	54
COMPLETED	38
NOT COMPLETED	16
Period Title: Concurrent Therapy (5 Weeks)
STARTED	38
Completed First Cycle	37
COMPLETED	37
NOT COMPLETED	1
Period Title: Concurrent Therapy (5 Weeks)
STARTED	37
Went on to Cycle 2 +	27
COMPLETED	27
NOT COMPLETED	10
Period Title: Concurrent Therapy (5 Weeks)
STARTED	54
COMPLETED	54
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Treatment (Radiation, Chemotherapy, Monoclonal Antibody)
Arm/Group Description	CONCURRENT THERAPY: Patients undergo hypofractionated radiation therapy 5 days a week beginning on Day 0. Patients also receive temozolomide PO QD and bevacizumab IV over 30-90 minutes once every 2 weeks beginning on Days -3 to 0. Treatment continues for 5 weeks in the absence of disease progression or unacceptable toxicity. ADJUVANT THERAPY: Beginning 2 weeks after completion of radiation therapy, patients receive temozolomide PO QD for 6 weeks and bevacizumab IV over 30-90 minutes once every 2 weeks. Courses repeat every 8 weeks in the absence of disease progression or unacceptable toxicity. Temozolomide: Given PO Hypofractionated Radiation Therapy: Undergo hypofractionated radiation therapy Bevacizumab: Given IV Questionnaire administration: Ancillary studies
Overall Participants	54
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	46 85.2%
>=65 years	8 14.8%
Sex: Female, Male (Count of Participants)
Female	17 31.5%
Male	37 68.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	6 11.1%
Not Hispanic or Latino	48 88.9%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	1 1.9%
Black or African American	3 5.6%
White	48 88.9%
More than one race	2 3.7%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	54 100%
Bevacizumab-Naive Recurrent GBM (Count of Participants)
Count of Participants [Participants]	8 14.8%
Bevacizumab-Exposed Recurrent GBM (Count of Participants)
Count of Participants [Participants]	36 66.7%
Bevacizumab-Naive Recurrent Anaplastic Glioma (Count of Participants)
Count of Participants [Participants]	3 5.6%
Bevacizumab-Exposed Recurrent Anaplastic Glioma (Count of Participants)
Count of Participants [Participants]	7 13%

Outcome Measures

1. Primary Outcome

Title	Overall Survival (OS) for Patients With Recurrent High Grade Malignant Gliomas Treated With Concurrent Radiation, Temozolomide, and Bevacizumab Followed by Adjuvant Temozolomide and Bevacizumab.
Description	Data will be analyzed using Kaplan-Meier curves. OS is defined as the time from first re-irradiation treatment until death from any cause.
Time Frame	From treatment initiation and every 8 weeks for up to 53.5 months

Outcome Measure Data

Analysis Population Description

All patients were eligible for this outcome measure with 2 patients not experiencing the event at time of analysis.

Arm/Group Title	Treatment (Radiation, Chemotherapy, Monoclonal Antibody)
Arm/Group Description	CONCURRENT THERAPY: Patients undergo hypofractionated radiation therapy 5 days a week beginning on Day 0. Patients also receive temozolomide PO QD and bevacizumab IV over 30-90 minutes once every 2 weeks beginning on Days -3 to 0. Treatment continues for 5 weeks in the absence of disease progression or unacceptable toxicity. ADJUVANT THERAPY: Beginning 2 weeks after completion of radiation therapy, patients receive temozolomide PO QD for 6 weeks and bevacizumab IV over 30-90 minutes once every 2 weeks. Courses repeat every 8 weeks in the absence of disease progression or unacceptable toxicity. Temozolomide: Given PO Hypofractionated Radiation Therapy: Undergo hypofractionated radiation therapy Bevacizumab: Given IV Questionnaire administration: Ancillary studies
Measure Participants	54
Median (95% Confidence Interval) [Months]	8.5

2. Secondary Outcome

Title	Patient Reported Quality of Life (QOL)
Description	Questionnaires were completed before treatment (baseline) at the end of treatment (EOT) and after Cycle 1 and Cycle 2 of treatment (Initial phase of treatment =5 weeks + approximately 2 weeks recovery then adjuvant therapy where 1 cycle = 8 weeks). The following questionnaires were completed by patients to evaluate quality of life (QOL) at these timepoints: FACT-Fatigue - scores from 1 to 4 with 1=not at all and 4=very much, the higher the score the more fatigue reported by the patient. FACT-Brain (FACT Br) which included - Physcial Well-being (PWB), Social/Family Well-being (SWB), Emotional Well-being (EWB), and Functional Well-being (FWB). Patients gave scores from 0 to 4 with 0=not at all and 4=very much, the higher the score the better the QOL reported by the patient.
Time Frame	Completed before treatment (baseline) after Cycle 1 (approximately week 15) and Cycle 2 (approximately week 23)of adjuvant treatment and at the end of treatment (up to 7 cycles of adjuvant treatment, where 1 cycle =8 weeks)

Outcome Measure Data

Analysis Population Description

Only patients where sufficient data was collected for analysis were considered evaluable for this endpoint and included.

Arm/Group Title	Treatment (Radiation, Chemotherapy, Monoclonal Antibody)
Arm/Group Description	CONCURRENT THERAPY: Patients undergo hypofractionated radiation therapy 5 days a week beginning on Day 0. Patients also receive temozolomide PO QD and bevacizumab IV over 30-90 minutes once every 2 weeks beginning on Days -3 to 0. Treatment continues for 5 weeks in the absence of disease progression or unacceptable toxicity. ADJUVANT THERAPY: Beginning 2 weeks after completion of radiation therapy, patients receive temozolomide PO QD for 6 weeks and bevacizumab IV over 30-90 minutes once every 2 weeks. Courses repeat every 8 weeks in the absence of disease progression or unacceptable toxicity. Temozolomide: Given PO Hypofractionated Radiation Therapy: Undergo hypofractionated radiation therapy Bevacizumab: Given IV Questionnaire administration: Ancillary studies
Measure Participants	42
FACT-BR Total : Baseline	130.4 (29.6)
FACT-BR Total : EOT	106.9 (61.4)
FACT-BR Total : Post Cycle 1	133.0 (18.8)
FACT-BR Total : Post Cycle 2	131.4 (10.2)
FACT-BR PWB : Baseline	22.0 (5.0)
FACT-BR PWB : EOT	21.6 (5.0)
FACT-BR PWB : Post Cycle 1	21.7 (4.4)
FACT-BR PWB : Post Cycle 2	21.1 (3.9)
FACT-BR SWB : Baseline	22.2 (5.4)
FACT-BR SWB : EOT	22.9 (4.3)
FACT-BR SWB : Post Cycle 1	23.0 (3.2)
FACT-BR SWB : Post Cycle 2	23.7 (3.0)
FACT-BR EWB : Baseline	15.9 (5.7)
FACT-BR EWB : EOT	16.5 (4.9)
FACT-BR EWB : Post Cycle 1	17.2 (3.3)
FACT-BR EWB : Post Cycle 2	17.7 (3.0)
FACT-FWB : Baseline	15.9 (6.9)
FACT-FWB : EOT	17.8 (4.8)
FACT-FWB : Post Cycle 1	17.0 (4.8)
FACT-FWB: Post Cycle 2	18.3 (3.3)
FACIT-Fatigue: Baseline	35.6 (10.3)
FACIT-Fatigue: EOT	30.3 (12.5)
FACIT-Fatigue: Post Cycle 1	34.4 (7.7)
FACIT-Fatigue: Post Cycle 2	36.2 (7.9)

3. Secondary Outcome

Title	Safety Profile for Patients With Recurrent High Grade Malignant Gliomas Treated With Concurrent Radiation, Temozolomide, and Bevacizumab Followed by Adjuvant Temozolomide and Bevacizumab
Description	Toxicity will be assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 criteria on Day 1 of every treatment cycle and by patient report while on study treatment and up to 30 days after the last treatment. Grade 1 - 4 adverse events (AE) where the relationship between the AE and at least one of the study drugs were considered to be definite, probable or possible, were collected and graded as: Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE
Time Frame	Completed weekly during initial phase of 5 weeks and 2 weeks recovery, then every cycle during adjuvant therapy where 1 cycle =8 weeks (for up to 7 cycles)

Outcome Measure Data

Analysis Population Description

All patients that received at least one dose of treatment on study were eligible for this outcome measure

Arm/Group Title	Treatment (Radiation, Chemotherapy, Monoclonal Antibody)
Arm/Group Description	CONCURRENT THERAPY: Patients undergo hypofractionated radiation therapy 5 days a week beginning on Day 0. Patients also receive temozolomide PO QD and bevacizumab IV over 30-90 minutes once every 2 weeks beginning on Days -3 to 0. Treatment continues for 5 weeks in the absence of disease progression or unacceptable toxicity. ADJUVANT THERAPY: Beginning 2 weeks after completion of radiation therapy, patients receive temozolomide PO QD for 6 weeks and bevacizumab IV over 30-90 minutes once every 2 weeks. Courses repeat every 8 weeks in the absence of disease progression or unacceptable toxicity. Temozolomide: Given PO Hypofractionated Radiation Therapy: Undergo hypofractionated radiation therapy Bevacizumab: Given IV Questionnaire administration: Ancillary studies
Measure Participants	54
Lymphopenia : Grade 1	4 7.4%
Lymphopenia : Grade 2	12 22.2%
Lymphopenia : Grade 3	4 7.4%
Lymphopenia : Grade 4	1 1.9%
Fatigue : Grade 1	9 16.7%
Fatigue : Grade 2	5 9.3%
Fatigue : Grade 3	1 1.9%
Fatigue : Grade 4	0 0%
Thrombocytopenia : Grade 1	8 14.8%
Thrombocytopenia : Grade 2	1 1.9%
Thrombocytopenia : Grade 3	2 3.7%
Thrombocytopenia : Grade 4	1 1.9%
Anemia : Grade 1	7 13%
Anemia : Grade 2	1 1.9%
Anemia : Grade 3	1 1.9%
Anemia : Grade 4	0 0%
Constipation : Grade 1	8 14.8%
Constipation : Grade 2	1 1.9%
Constipation : Grade 3	0 0%
Constipation : Grade 4	0 0%
Hypertension : Grade 1	0 0%
Hypertension : Grade 2	6 11.1%
Hypertension : Grade 3	1 1.9%
Hypertension : Grade 4	0 0%
Neutropenia : Grade 1	2 3.7%
Neutropenia : Grade 2	3 5.6%
Neutropenia : Grade 3	0 0%
Neutropenia : Grade 4	0 0%
Epistaxis : Grade 1	3 5.6%
Epistaxis : Grade 2	0 0%
Epistaxis : Grade 3	0 0%
Epistaxis : Grade 4	0 0%
Thromboembolism : Grade 1	0 0%
Thromboembolism : Grade 2	1 1.9%
Thromboembolism : Grade 3	1 1.9%
Thromboembolism : Grade 4	0 0%
Proteinuria : Grade 1	0 0%
Proteinuria : Grade 2	0 0%
Proteinuria : Grade 3	2 3.7%
Proteinuria : Grade 4	0 0%
Wound Complication : Grade 1	0 0%
Wound Complication : Grade 2	0 0%
Wound Complication : Grade 3	2 3.7%
Wound Complication : Grade 4	0 0%

4. Secondary Outcome

Title	Percentage of Patients With Progression Free Survival (PFS) at 6 Months and 12 Months
Description	Progression Free Survival is defined as the time from the first study treatment to the first occurrence of disease progression or death. Data will be analyzed using Kaplan-Meier curves. Tumor measurements and assessments will be based on Updated Response Assessment Criteria of High Grade Gliomas- Neuro-Oncology Working Group (RANO criteria). Tumor assessments may include either a CT or MRI scan of the brain, however the same method should be used throughout the treatment period for each patient. In general, progressive disease is defined as any of the following: ≥ 25% increase in T1 gadolinium enhancing disease, increase in T2/Flair, new lesions present or decrease in clinical status
Time Frame	At 6 and 12 months after the start of treatment

Outcome Measure Data

Analysis Population Description

Only evaluable patients that completed RT treatment, with follow up imaging and data for progression were included in this endpoint.

Arm/Group Title	Treatment (Radiation, Chemotherapy, Monoclonal Antibody)
Arm/Group Description	CONCURRENT THERAPY: Patients undergo hypofractionated radiation therapy 5 days a week beginning on Day 0. Patients also receive temozolomide PO QD and bevacizumab IV over 30-90 minutes once every 2 weeks beginning on Days -3 to 0. Treatment continues for 5 weeks in the absence of disease progression or unacceptable toxicity. ADJUVANT THERAPY: Beginning 2 weeks after completion of radiation therapy, patients receive temozolomide PO QD for 6 weeks and bevacizumab IV over 30-90 minutes once every 2 weeks. Courses repeat every 8 weeks in the absence of disease progression or unacceptable toxicity. Temozolomide: Given PO Hypofractionated Radiation Therapy: Undergo hypofractionated radiation therapy Bevacizumab: Given IV Questionnaire administration: Ancillary studies
Measure Participants	42
6 Months	48
12 Months	12

5. Post-Hoc Outcome

Title	Response of Patients With Recurrent High Grade Malignant Gliomas Treated With Concurrent Radiation, Temozolomide, and Bevacizumab Followed by Adjuvant Temozolomide and Bevacizumab
Description	Best response is measured by CT/MRI and assessed by Updated Response Assessment Criteria of High Grade Gliomas- Neuro-Oncology Working Group (RANO criteria). In general best response will be defined as one of the following: Complete Response: No T1 gadolinium enhancing disease, stable or decreasing T2/FLAIR, no new lesions, no corticosteroid use and stable or increasing clinical status Partial Response: ≥ 50% decrease in T1 gadolinium enhancing disease, stable or decreasing T2/FLAIR, no new lesions,stable or decreasing use of corticosteroids, and stable or increasing clinical status Stable Disease: < 50% decrease but < 25% increase T1 gadolinium enhancing disease, stable or decreasing T2/FLAIR, no new lesions,stable or decreasing use of corticosteroids, and stable or increasing clinical status Progressive Disease is any of the following: ≥ 25% increase in T1 gadolinium enhancing disease, increase in T2/Flair, new lesions present or decrease in clinical status
Time Frame	Every 8 weeks from the start of study treatment. Median time from beginning of initial radiation treatment was 25.3 months (range 8.1-82.4 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Radiation, Chemotherapy, Monoclonal Antibody)
Arm/Group Description	CONCURRENT THERAPY: Patients undergo hypofractionated radiation therapy 5 days a week beginning on Day 0. Patients also receive temozolomide PO QD and bevacizumab IV over 30-90 minutes once every 2 weeks beginning on Days -3 to 0. Treatment continues for 5 weeks in the absence of disease progression or unacceptable toxicity. ADJUVANT THERAPY: Beginning 2 weeks after completion of radiation therapy, patients receive temozolomide PO QD for 6 weeks and bevacizumab IV over 30-90 minutes once every 2 weeks. Courses repeat every 8 weeks in the absence of disease progression or unacceptable toxicity. Temozolomide: Given PO Hypofractionated Radiation Therapy: Undergo hypofractionated radiation therapy Bevacizumab: Given IV Questionnaire administration: Ancillary studies
Measure Participants	54
Complete Response	3 5.6%
Partial Response	10 18.5%
Stable Disease	28 51.9%
Progressive Disease	9 16.7%
Not Evaluable	4 7.4%

6. Post-Hoc Outcome

Title	Median Progression Free Survival (PFS) for Patients With Recurrent High Grade Malignant Gliomas Treated With Concurrent Radiation, Temozolomide, and Bevacizumab Followed by Adjuvant Temozolomide and Bevacizumab
Description	Progression Free Survival (PFS) is defined as the time from the first study treatment to the first occurrence of disease progression or death. Data will be analyzed using Kaplan-Meier curves. Tumor measurements and assessments will be based on Updated Response Assessment Criteria of High Grade Gliomas- Neuro-Oncology Working Group (RANO criteria). Tumor assessments may include either a CT or MRI scan of the brain, however the same method should be used throughout the treatment period for each patient. In general, progressive disease is defined as any of the following: ≥ 25% increase in T1 gadolinium enhancing disease, increase in T2/Flair, new lesions present or decrease in clinical status.
Time Frame	Range from treatment initiation 0.4-26.9 months

Outcome Measure Data

Analysis Population Description

Only evaluable patients that completed RT treatment, with follow up imaging and data for progression were included in this endpoint.

Arm/Group Title	Treatment (Radiation, Chemotherapy, Monoclonal Antibody)
Arm/Group Description	CONCURRENT THERAPY: Patients undergo hypofractionated radiation therapy 5 days a week beginning on Day 0. Patients also receive temozolomide PO QD and bevacizumab IV over 30-90 minutes once every 2 weeks beginning on Days -3 to 0. Treatment continues for 5 weeks in the absence of disease progression or unacceptable toxicity. ADJUVANT THERAPY: Beginning 2 weeks after completion of radiation therapy, patients receive temozolomide PO QD for 6 weeks and bevacizumab IV over 30-90 minutes once every 2 weeks. Courses repeat every 8 weeks in the absence of disease progression or unacceptable toxicity. Temozolomide: Given PO Hypofractionated Radiation Therapy: Undergo hypofractionated radiation therapy Bevacizumab: Given IV Questionnaire administration: Ancillary studies
Measure Participants	42
Median (Full Range) [Months]	5.5

7. Post-Hoc Outcome

Title	Overall Survival (OS) at 6 Months and 12 Months for Patients With Recurrent High Grade Malignant Gliomas Treated With Concurrent Radiation, Temozolomide, and Bevacizumab Followed by Adjuvant Temozolomide and Bevacizumab.
Description	Data will be analyzed using Kaplan-Meier curves. OS is defined as the time from first re-irradiation treatment until death from any cause. Percentages of patients alive at that 6 months and 12 months will be calculated from the Kaplan-Meier curve.
Time Frame	At 6 and 12 months from start of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Radiation, Chemotherapy, Monoclonal Antibody)
Arm/Group Description	CONCURRENT THERAPY: Patients undergo hypofractionated radiation therapy 5 days a week beginning on Day 0. Patients also receive temozolomide PO QD and bevacizumab IV over 30-90 minutes once every 2 weeks beginning on Days -3 to 0. Treatment continues for 5 weeks in the absence of disease progression or unacceptable toxicity. ADJUVANT THERAPY: Beginning 2 weeks after completion of radiation therapy, patients receive temozolomide PO QD for 6 weeks and bevacizumab IV over 30-90 minutes once every 2 weeks. Courses repeat every 8 weeks in the absence of disease progression or unacceptable toxicity. Temozolomide: Given PO Hypofractionated Radiation Therapy: Undergo hypofractionated radiation therapy Bevacizumab: Given IV Questionnaire administration: Ancillary studies
Measure Participants	54
6 Months	67
12 Months	28

Adverse Events

Time Frame	Adverse events were collected from the first day of treatment until 30 days after the last treatment on study for up to approximately 67 weeks for any patient. Concurrent therapy was 5 weeks in length followed by 2 weeks recovery and then adjuvant therapy where 1 cycle = 8 weeks and range of cycles completed 0-7.
Arm/Group Title	Treatment (Radiation, Chemotherapy, Monoclonal Antibody)
Arm/Group Description	CONCURRENT THERAPY: Patients undergo hypofractionated radiation therapy 5 days a week beginning on Day 0. Patients also receive temozolomide PO QD and bevacizumab IV over 30-90 minutes once every 2 weeks beginning on Days -3 to 0. Treatment continues for 5 weeks in the absence of disease progression or unacceptable toxicity. ADJUVANT THERAPY: Beginning 2 weeks after completion of radiation therapy, patients receive temozolomide PO QD for 6 weeks and bevacizumab IV over 30-90 minutes once every 2 weeks. Courses repeat every 8 weeks in the absence of disease progression or unacceptable toxicity. Temozolomide: Given PO Hypofractionated Radiation Therapy: Undergo hypofractionated radiation therapy Bevacizumab: Given IV Questionnaire administration: Ancillary studies
All Cause Mortality
	Treatment (Radiation, Chemotherapy, Monoclonal Antibody)
	Affected / at Risk (%)	# Events
Total	52/54 (96.3%)
Serious Adverse Events
	Treatment (Radiation, Chemotherapy, Monoclonal Antibody)
	Affected / at Risk (%)	# Events
Total	20/54 (37%)
Gastrointestinal disorders
Hemorrhoidal hemorrhage	1/54 (1.9%)
General disorders
Death NOS	5/54 (9.3%)
Infections and infestations
Wound Infection	1/54 (1.9%)
Upper Respiratory Infection	1/54 (1.9%)
Hepatic Infection	1/54 (1.9%)
Injury, poisoning and procedural complications
Fall	1/54 (1.9%)
Wound Complication	1/54 (1.9%)
Investigations
Platelet Count Decreased	1/54 (1.9%)
Metabolism and nutrition disorders
Anorexia	1/54 (1.9%)
Dehydration	1/54 (1.9%)
Hyponatremia	1/54 (1.9%)
Musculoskeletal and connective tissue disorders
Generalized Muscle Weakness	1/54 (1.9%)
Muscle Weakness Right-sided	1/54 (1.9%)
Nervous system disorders
Seizure	4/54 (7.4%)
Depressed Level of Consciousness	1/54 (1.9%)
Headache	1/54 (1.9%)
Respiratory, thoracic and mediastinal disorders
Hiccups	1/54 (1.9%)
Vascular disorders
Thromboembolic Event	2/54 (3.7%)
Other (Not Including Serious) Adverse Events
	Treatment (Radiation, Chemotherapy, Monoclonal Antibody)
	Affected / at Risk (%)	# Events
Total	54/54 (100%)
Blood and lymphatic system disorders
Anemia	12/54 (22.2%)
Blood and lymphatic system disorders - Other, specify	1/54 (1.9%)
Cardiac disorders
Sinus bradycardia	1/54 (1.9%)
Sinus tachycardia	2/54 (3.7%)
Ear and labyrinth disorders
Ear and labyrinth disorders - Other, specify	1/54 (1.9%)
Ear pain	1/54 (1.9%)
Hearing impaired	1/54 (1.9%)
Vertigo	1/54 (1.9%)
Endocrine disorders
Hypothyroidism	2/54 (3.7%)
Eye disorders
Blurred vision	9/54 (16.7%)
Dry eye	1/54 (1.9%)
Extraocular muscle paresis	1/54 (1.9%)
Eye disorders - Other, specify	2/54 (3.7%)
Watering eyes	1/54 (1.9%)
Gastrointestinal disorders
Abdominal distension	1/54 (1.9%)
Abdominal pain	1/54 (1.9%)
Anal hemorrhage	1/54 (1.9%)
Constipation	21/54 (38.9%)
Diarrhea	3/54 (5.6%)
Dry mouth	1/54 (1.9%)
Dyspepsia	3/54 (5.6%)
Dysphagia	2/54 (3.7%)
Esophagitis	1/54 (1.9%)
Fecal incontinence	3/54 (5.6%)
Gastroesophageal reflux disease	4/54 (7.4%)
Gastrointestinal disorders - Other, specify	1/54 (1.9%)
Mucositis oral	3/54 (5.6%)
Nausea	14/54 (25.9%)
Oral pain	1/54 (1.9%)
Vomiting	6/54 (11.1%)
General disorders
Chills	1/54 (1.9%)
Edema limbs	2/54 (3.7%)
Fatigue	31/54 (57.4%)
Fever	1/54 (1.9%)
Gait disturbance	15/54 (27.8%)
Infusion site extravasation	1/54 (1.9%)
Irritability	2/54 (3.7%)
Localized edema	2/54 (3.7%)
Malaise	1/54 (1.9%)
Pain	6/54 (11.1%)
Sudden death NOS	1/54 (1.9%)
Immune system disorders
Immune system disorders - Other, specify	1/54 (1.9%)
Infections and infestations
Infections and infestations - Other, specify	2/54 (3.7%)
Meningitis	1/54 (1.9%)
Peripheral nerve infection	1/54 (1.9%)
Sinusitis	1/54 (1.9%)
Tooth infection	1/54 (1.9%)
Upper respiratory infection	1/54 (1.9%)
Urinary tract infection	2/54 (3.7%)
Injury, poisoning and procedural complications
Bruising	1/54 (1.9%)
Dermatitis radiation	7/54 (13%)
Fall	3/54 (5.6%)
Fracture	1/54 (1.9%)
Wound dehiscence	1/54 (1.9%)
Investigations
Alanine aminotransferase increased	4/54 (7.4%)
Alkaline phosphatase increased	2/54 (3.7%)
Aspartate aminotransferase increased	6/54 (11.1%)
Blood bilirubin increased	3/54 (5.6%)
Cholesterol high	2/54 (3.7%)
Creatinine increased	3/54 (5.6%)
INR increased	1/54 (1.9%)
Investigations - Other, specify	1/54 (1.9%)
Lymphocyte count decreased	27/54 (50%)
Lymphocyte count increased	1/54 (1.9%)
Neutrophil count decreased	2/54 (3.7%)
Platelet count decreased	20/54 (37%)
Urine output decreased	1/54 (1.9%)
Weight gain	3/54 (5.6%)
Weight loss	10/54 (18.5%)
White blood cell decreased	10/54 (18.5%)
Metabolism and nutrition disorders
Anorexia	11/54 (20.4%)
Dehydration	5/54 (9.3%)
Hyperglycemia	14/54 (25.9%)
Hyperkalemia	1/54 (1.9%)
Hypertriglyceridemia	2/54 (3.7%)
Hypoalbuminemia	8/54 (14.8%)
Hypocalcemia	8/54 (14.8%)
Hypoglycemia	3/54 (5.6%)
Hypokalemia	5/54 (9.3%)
Hypomagnesemia	1/54 (1.9%)
Hyponatremia	4/54 (7.4%)
Musculoskeletal and connective tissue disorders
Arthralgia	3/54 (5.6%)
Back pain	1/54 (1.9%)
Joint range of motion decreased	1/54 (1.9%)
Joint range of motion decreased cervical spine	1/54 (1.9%)
Muscle weakness left-sided	7/54 (13%)
Muscle weakness lower limb	3/54 (5.6%)
Muscle weakness right-sided	7/54 (13%)
Muscle weakness upper limb	1/54 (1.9%)
Musculoskeletal and connective tissue disorder - Other, specify	2/54 (3.7%)
Myalgia	1/54 (1.9%)
Pain in extremity	1/54 (1.9%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify	4/54 (7.4%)
Nervous system disorders
Akathisia	1/54 (1.9%)
Amnesia	2/54 (3.7%)
Ataxia	8/54 (14.8%)
Cognitive disturbance	1/54 (1.9%)
Dizziness	5/54 (9.3%)
Dysarthria	3/54 (5.6%)
Dysgeusia	2/54 (3.7%)
Dysphasia	13/54 (24.1%)
Edema cerebral	7/54 (13%)
Encephalopathy	1/54 (1.9%)
Facial nerve disorder	6/54 (11.1%)
Headache	20/54 (37%)
Hypersomnia	1/54 (1.9%)
Lethargy	2/54 (3.7%)
Memory impairment	11/54 (20.4%)
Movements involuntary	1/54 (1.9%)
Nervous system disorders - Other, specify	9/54 (16.7%)
Paresthesia	5/54 (9.3%)
Peripheral sensory neuropathy	4/54 (7.4%)
Presyncope	1/54 (1.9%)
Pyramidal tract syndrome	7/54 (13%)
Seizure	20/54 (37%)
Somnolence	2/54 (3.7%)
Stroke	1/54 (1.9%)
Tremor	5/54 (9.3%)
Psychiatric disorders
Anxiety	13/54 (24.1%)
Confusion	9/54 (16.7%)
Depression	13/54 (24.1%)
Hallucinations	2/54 (3.7%)
Insomnia	10/54 (18.5%)
Personality change	2/54 (3.7%)
Psychiatric disorders - Other, specify	1/54 (1.9%)
Psychosis	1/54 (1.9%)
Renal and urinary disorders
Chronic kidney disease	1/54 (1.9%)
Hematuria	1/54 (1.9%)
Proteinuria	6/54 (11.1%)
Renal and urinary disorders - Other, specify	2/54 (3.7%)
Urinary frequency	1/54 (1.9%)
Urinary incontinence	7/54 (13%)
Urinary retention	2/54 (3.7%)
Urinary tract pain	1/54 (1.9%)
Urinary urgency	3/54 (5.6%)
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	4/54 (7.4%)
Aspiration	1/54 (1.9%)
Cough	4/54 (7.4%)
Dyspnea	1/54 (1.9%)
Epistaxis	3/54 (5.6%)
Nasal congestion	1/54 (1.9%)
Postnasal drip	1/54 (1.9%)
Pulmonary hypertension	1/54 (1.9%)
Respiratory, thoracic and mediastinal disorders - Other, specify	1/54 (1.9%)
Sneezing	1/54 (1.9%)
Sore throat	3/54 (5.6%)
Skin and subcutaneous tissue disorders
Alopecia	16/54 (29.6%)
Nail loss	1/54 (1.9%)
Pruritus	2/54 (3.7%)
Purpura	1/54 (1.9%)
Rash acneiform	2/54 (3.7%)
Rash maculo-papular	3/54 (5.6%)
Skin and subcutaneous tissue disorders - Other, specify	1/54 (1.9%)
Urticaria	1/54 (1.9%)
Vascular disorders
Hypertension	20/54 (37%)
Thromboembolic event	4/54 (7.4%)

Limitations/Caveats

The study was closed to accrual before the accrual goal was met due to slow accrual

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.