Bevacizumab, Temozolomide, and External Beam Radiation Therapy as First-Line Therapy in Treating Patients With Newly Diagnosed Glioblastoma Multiforme or Gliosarcoma

• Sponsor: Jonsson Comprehensive Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT01013285
• Collaborator: (none)
• Enrollment: 70
• Location: 1
• Arm: 1
• Duration (Months): 110
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

RATIONALE: Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. 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. Radiation therapy uses high energy x-rays to kill tumor cells. Giving bevacizumab together with temozolomide and radiation therapy may kill more tumor cells.

PURPOSE: This phase II trial is studying the side effects and how well giving bevacizumab together with temozolomide and external beam radiation therapy works when given as first-line therapy in treating patients with newly diagnosed glioblastoma multiforme or gliosarcoma.

Condition or Disease	Intervention/Treatment	Phase
Brain and Central Nervous System Tumors	Biological: bevacizumab; Drug: temozolomide; Radiation: external beam radiation therapy	Phase 2

Detailed Description

OBJECTIVES:

Primary

• To investigate the safety and tolerability of bevacizumab in combination with temozolomide and external beam fractionated regional radiotherapy as first-line treatment in patients with newly diagnosed glioblastoma multiforme or gliosarcoma. (Pilot phase)

• To estimate the overall survival of patients treated with this regimen. (Expansion phase)

Secondary

• To further investigate the safety and tolerability of this regimen in these patients. (Expansion phase)

• To isolate DNA, RNA, and protein from frozen and paraffin-embedded archival tumor samples for evaluations, such as immunohistochemical pathway profiling of vascular endothelial growth factor (VEGF)-dependent angiogenic pathways, gene expression microarray, and O-6 methylguanine DNA methyltransferase (MGMT) promoter methylation status to define important molecular features of treatment response.

OUTLINE: This is a multicenter study.

Patients undergo external beam fractionated regional radiotherapy once daily 5 days a week for 6 weeks and receive concurrent oral temozolomide once daily for 6 weeks. Patients also receive bevacizumab IV over 30-90 minutes every 2 weeks beginning on the first day of radiotherapy and continuing in the absence of disease progression or unacceptable toxicity. Beginning 2-5 weeks after completion of radiotherapy, patients receive oral temozolomide on days 1-5. Treatment with temozolomide repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.

Blood and frozen and paraffin-embedded tumor tissue samples are collected for biomarker and genetic analysis.

After completion of study treatment, patients are followed up periodically.

Study Design

• Study Type: Interventional
• Actual Enrollment: 70 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Trial of Bevacizumab in Combination With Temozolomide and Regional Radiation Therapy for Upfront Treatment of Patients With Newly-diagnosed Glioblastoma Multiforme
• Study Start Date: Jun 1, 2006
• Actual Primary Completion Date: Oct 1, 2013
• Actual Study Completion Date: Aug 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: bevacizumab, temozolomide, external beam radiation	Biological: bevacizumab; Drug: temozolomide; Radiation: external beam radiation therapy

Outcome Measures

Primary Outcome Measures

1. Overall Survival [2 years]

Secondary Outcome Measures

1. Time to Disease Progression [2 years]

   Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

2. Progression-free Survival at 6 Months [6 months]

   participants who were alive and disease progression free at 6 months

3. Radiographic Response (When Evaluable) [2 years]

   Radiation therapy (RT) median from diagnosis to RT. Patients will have brain MRI evaluation of response and progression every 8 weeks starting from the day 56 scan obtained 2 weeks after completion of radiation and daily temozolomide and assessment will be conducted on a 7-point scale. This scale is expected to be more useful in this study because many newly-diagnosed patients are likely not to have evaluable disease due to gross total resections. Determination of whether progression occurs based on the day 56 scan will take into account the untreated window between baseline MRI and day of 1 of study. 7 Point Likert Scale: 3 to -3, 3 means complete resolution of tumor, and -3 means new lesion. A -2 or -3 assessment will be taken as tumor progression. complete resolution of tumor: 3 tumor resolved 3 tumor definitely smaller: 2 tumor probably smaller: 1 tumor unchanged: 0 tumor probably worse: -1 tumor definitely worse: -2 New Lesion: -3

4. Median Overall Survival (OS) Based on the MGMT Promoter Methylation Status [2 years]

   IDH1 and MGMT methylation are important independent prognostic biomarkers that have to be included in a Cox regression model. In addition, subgroup analysis could reveal differential sensitivities to the treatment arm. The MGMT promoter methylation status, IDH1 mutation status were not available for all of the control samples. Therefore, only the samples with both info available were included in the analysis. Baseline analysis results are included in the Baseline Characteristics module.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Histologically confirmed intracranial glioblastoma multiforme (GBM) or gliosarcoma.

• Prior histologic diagnosis of low-grade glioma allowed provided it has been upgraded to GBM after repeat resection

• Has undergone surgery to collect tumor tissue 3-6 weeks ago

• Measurable or assessable disease is not required

• Karnofsky performance status 60-100%

• Life expectancy > 8 weeks

• White Blood Cell (WBC) ≥ 3,000/mm³

• Absolute Neutrophil Count (ANC) ≥ 1,500/mm³

• Platelet count ≥ 100,000/mm³

• Hemoglobin ≥ 10 g/dL (transfusion allowed)

• Serum Glutamate Oxaloacetate Transaminase (SGOT) < 2.5 times upper limit of normal (ULN)

• Bilirubin < 2.5 times ULN

• INR (international normalized ratio) ≤ 1.5 times ULN (except if on therapeutic anticoagulation therapy)

• aPTT (activated partial thromboplastin time) ≤ 1.5 times ULN (except if on therapeutic anticoagulation therapy)

• Creatinine < 1.5 mg/dL

• Urine protein:creatinine ratio < 1.0

• Negative pregnancy test

• Fertile patients must use effective contraception

• More than 28 days since prior major surgical procedures or open biopsy (other than craniotomy)

• More than 7 days since prior minor surgical procedures (e.g., placement of PortoCath (port-a-cath - a port placed under the subjects skin), stereotactic biopsy, fine-needle aspirations, or core biopsies)

• More than 4 weeks since prior and no concurrent participation in another experimental drug study.

• Prior or concurrent corticosteroids, anti-epileptic drugs, analgesics, or other drugs to treat symptoms or prevent complications are allowed

• Concurrent full-dose warfarin or its equivalent (i.e., unfractionated and/or low molecular weight heparin) allowed

Exclusion Criteria:

• unstable angina

• BP > 150/100 mm Hg

• New York Heart Association (NYHA) class II-IV congestive heart failure

• myocardial infarction within the past 6 months

• stroke within the past 6 months

• clinically significant peripheral vascular disease

• evidence of bleeding diathesis or coagulopathy

• intracerebral abscess within past 6 months

• abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months

• serious, non-healing wound, ulcer, or bone fracture

• Any wound requiring surgical intervention (including scalp wounds requiring cranioplasty) allowed provided the wound is clean and without further infection post-surgical intervention

• significant traumatic injury within the past 28 days

• concurrent serious uncontrolled medical illness including, but not limited to, the following:

• Ongoing or active infection requiring IV antibiotics

• Psychiatric illness/social situation that would limit compliance with study requirements

• Disorders associated with significant immunocompromised state (e.g., HIV, systemic lupus erythematosus)

• other cancer within the past 3 years, except nonmelanoma skin cancer or carcinoma in situ of the cervix

• disease that would obscure toxicity or dangerously alter drug metabolism

• significant medical illness that, in the investigator's opinion, cannot be adequately controlled with appropriate therapy or would compromise the patient's ability to tolerate study therapy

• prior radiotherapy to the brain

• prior cytotoxic or non-cytotoxic drug therapy or experimental drug therapy for the brain tumor

• prior Gliadel wafers

• concurrent participation in any other clinical trial

• concurrent GM-CSF (granulocyte-macrophage colony-stimulating factor)

• concurrent stereotactic radiosurgery or brachytherapy

• concurrent major surgical procedure

• other concurrent anticancer therapy, including chemotherapy, hormonal therapy, radiotherapy, or immunotherapy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Jonsson Comprehensive Cancer Center, University of California, Los Angeles (UCLA)	Los Angeles	California	United States	90095-1781

Sponsors and Collaborators

• Jonsson Comprehensive Cancer Center

Investigators

• Principal Investigator: Albert Lai, MD, Ronald Reagan University of California, Los Angeles (UCLA) Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Jonsson Comprehensive Cancer Center
• ClinicalTrials.gov Identifier: NCT01013285
• Other Study ID Numbers: 11-000558; UCLA-0604016; AVF3770s; CDR0000628787; GENENTECH-UCLA-0604016
• First Posted: Nov 13, 2009
• Last Update Posted: Sep 21, 2020
• Last Verified: Apr 1, 2016

• Keywords provided by Jonsson Comprehensive Cancer Center: adult giant cell glioblastoma; adult gliosarcoma; adult glioblastoma
• Additional relevant MeSH terms: Glioblastoma; Gliosarcoma; Nervous System Neoplasms; Central Nervous System Neoplasms; Bevacizumab; Temozolomide

Study Results

Participant Flow

Recruitment Details	Seventy patients with newly diagnosed Glioblastoma Multiforme were enrolled between August 2006 and November 2008 from two participating sites, comprised of University of California, Los Angeles (UCLA) and Kaiser Permanente Los Angeles.
Pre-assignment Detail	Control cohort was derived from University of California, Los Angeles/Kaiser Permanente Los Angeles patients treated with first-line radiation therapy and temozolomide who had mostly received bevacizumab at recurrence.

Arm/Group Title	Treatment Arm	Historical Control UCLA/KPLA
Arm/Group Description	bevacizumab temozolomide external beam radiation therapy	A University of California, Los Angeles/Kaiser Permanente Los Angeles(KPLA) control cohort of newly diagnosed patients treated with first-line radiation therapy and temozolomide who had mostly received bevacizumab at recurrence was derived for comparison.
Period Title: Overall Study
STARTED	70	110
COMPLETED	22	21
NOT COMPLETED	48	89

Baseline Characteristics

Arm/Group Title	Treatment Arm	Historical Control UCLA/Kaiser	Total
Arm/Group Description	bevacizumab temozolomide external beam radiation therapy	A University of California, Los Angeles/Kaiser Permanente Los Angeles(KPLA) control cohort of newly diagnosed patients treated with first-line radiation therapy and temozolomide who had mostly received bevacizumab at recurrence was derived for comparison. Data excluded where records not complete	Total of all reporting groups
Overall Participants	70	110	180
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	57.4	59.4	59.305
Age, Customized (participants) [Number]
< 50 years	15 21.4%	30 27.3%	45 25%
>= 50 years	55 78.6%	80 72.7%	135 75%
Sex: Female, Male (Count of Participants)
Female	31 44.3%	40 36.4%	71 39.4%
Male	39 55.7%	70 63.6%	109 60.6%
Enrollment by Site (participants) [Number]
UCLA	38 54.3%	61 55.5%	99 55%
KPLA	32 45.7%	49 44.5%	81 45%
Karnofsky performance status (participants) [Number]
100	8 11.4%	13 11.8%	21 11.7%
90	27 38.6%	62 56.4%	89 49.4%
80	27 38.6%	23 20.9%	50 27.8%
70	5 7.1%	8 7.3%	13 7.2%
60	3 4.3%	4 3.6%	7 3.9%
Extent of surgery (participants) [Number]
Biopsy	2 2.9%	23 20.9%	25 13.9%
Subtotal resection	40 57.1%	40 36.4%	80 44.4%
Gross total resection	28 40%	47 42.7%	75 41.7%
Recursive partitioning analysis by class (participants) [Number]
III: MST 17.1	9 12.9%	27 24.5%	36 20%
IV: MST 11.2	32 45.7%	45 40.9%	77 42.8%
V: MST 7.5	29 41.4%	37 33.6%	66 36.7%
VI: MST 7.5	0 0%	1 0.9%	1 0.6%
Follow-up (years) [Median (Full Range) ]
Median (Full Range) [years]	24.2	41.8	36.616
Deaths (participants) [Number]
Number [participants]	48 68.6%	89 80.9%	137 76.1%
Recurrent treatment (participants) [Number]
Progressed	56 80%	96 87.3%	152 84.4%
Progressed with chemotherapy	39 55.7%	64 58.2%	103 57.2%
Progressed with bevacizumab	29 41.4%	57 51.8%	86 47.8%
MGMT (O-6-Methylguanine-DNA Methyltransferase) promoter methylation (participants) [Number]
Methylated	29 41.4%	28 25.5%	57 31.7%
Unmethylated	41 58.6%	43 39.1%	84 46.7%
IDH1 (Isocitrate dehydrogenase 1 ) mutational status (participants) [Number]
Wild type	65 92.9%	68 61.8%	133 73.9%
IDH1-R132H mutation	5 7.1%	3 2.7%	8 4.4%

Outcome Measures

1. Primary Outcome

Title	Overall Survival
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment Arm	Historical Control UCLA/KPLA
Arm/Group Description	bevacizumab temozolomide external beam radiation therapy	A University of California, Los Angeles/Kaiser Permanente Los Angeles(KPLA) control cohort of newly diagnosed patients treated with first-line radiation therapy and temozolomide who had mostly received bevacizumab at recurrence was derived for comparison.
Measure Participants	70	110
Median (95% Confidence Interval) [Months]	19.6	21.1

2. Secondary Outcome

Title	Time to Disease Progression
Description	Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment Arm	Historical Control UCLA/KPLA
Arm/Group Description	bevacizumab temozolomide external beam radiation therapy	A University of California, Los Angeles/Kaiser Permanente Los Angeles(KPLA) control cohort of newly diagnosed patients treated with first-line radiation therapy and temozolomide who had mostly received bevacizumab at recurrence was derived for comparison.
Measure Participants	70	110
Median (95% Confidence Interval) [Months]	13.6	7.6

3. Secondary Outcome

Title	Progression-free Survival at 6 Months
Description	participants who were alive and disease progression free at 6 months
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment Arm	Historical Control UCLA/KPLA
Arm/Group Description	bevacizumab temozolomide external beam radiation therapy	A University of California, Los Angeles/Kaiser Permanente Los Angeles(KPLA) control cohort of newly diagnosed patients treated with first-line radiation therapy and temozolomide who had mostly received bevacizumab at recurrence was derived for comparison.
Measure Participants	70	110
Number (95% Confidence Interval) [percentage of participants]	88.4 126.3%	58.3 53%

4. Secondary Outcome

Title	Radiographic Response (When Evaluable)
Description	Radiation therapy (RT) median from diagnosis to RT. Patients will have brain MRI evaluation of response and progression every 8 weeks starting from the day 56 scan obtained 2 weeks after completion of radiation and daily temozolomide and assessment will be conducted on a 7-point scale. This scale is expected to be more useful in this study because many newly-diagnosed patients are likely not to have evaluable disease due to gross total resections. Determination of whether progression occurs based on the day 56 scan will take into account the untreated window between baseline MRI and day of 1 of study. 7 Point Likert Scale: 3 to -3, 3 means complete resolution of tumor, and -3 means new lesion. A -2 or -3 assessment will be taken as tumor progression. complete resolution of tumor: 3 tumor resolved 3 tumor definitely smaller: 2 tumor probably smaller: 1 tumor unchanged: 0 tumor probably worse: -1 tumor definitely worse: -2 New Lesion: -3
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment Arm	Historical Control UCLA/KPLA
Arm/Group Description	bevacizumab temozolomide external beam radiation therapy	A University of California, Los Angeles/Kaiser Permanente Los Angeles(KPLA) control cohort of newly diagnosed patients treated with first-line radiation therapy and temozolomide who had mostly received bevacizumab at recurrence was derived for comparison.
Measure Participants	70	110
Median (90% Confidence Interval) [Weeks]	4.14	5

5. Secondary Outcome

Title	Median Overall Survival (OS) Based on the MGMT Promoter Methylation Status
Description	IDH1 and MGMT methylation are important independent prognostic biomarkers that have to be included in a Cox regression model. In addition, subgroup analysis could reveal differential sensitivities to the treatment arm. The MGMT promoter methylation status, IDH1 mutation status were not available for all of the control samples. Therefore, only the samples with both info available were included in the analysis. Baseline analysis results are included in the Baseline Characteristics module.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

Description: Kaplan-Meier analysis of overall survival was performed.

Arm/Group Title	Treatment Arm	Historical Control UCLA/KPLA
Arm/Group Description	bevacizumab temozolomide external beam radiation therapy	A University of California, Los Angeles/Kaiser Permanente Los Angeles(KPLA) control cohort of newly diagnosed patients treated with first-line radiation therapy and temozolomide who had mostly received bevacizumab at recurrence was derived for comparison.
Measure Participants	70	71
Median Overall survival of MGMT Methylated	24.7	26.7
Median Overall survival of MGMT Unmethylated	15.9	18.2

Adverse Events

Time Frame	Data collected through study completion, 2.25 years.
Adverse Event Reporting Description	period coinciding with Aug 23, 2006 - Nov 26, 2008
Arm/Group Title	Bevacizumab, Temozolomide, External Beam Radiation
Arm/Group Description	bevacizumab temozolomide external beam radiation therapy
All Cause Mortality
	Bevacizumab, Temozolomide, External Beam Radiation
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Bevacizumab, Temozolomide, External Beam Radiation
	Affected / at Risk (%)	# Events
Total	54/70 (77.1%)
Blood and lymphatic system disorders
leukopenia	1/70 (1.4%)	2
Nephritic proteinuria	1/70 (1.4%)	1
Nephrotic syndrome	1/70 (1.4%)	1
neutropenia	1/70 (1.4%)	2
Stroke	1/70 (1.4%)	1
thrombocytopenia	1/70 (1.4%)	2
Transient Ischemic Attack	1/70 (1.4%)	1
Cardiac disorders
congestive heart failure	1/70 (1.4%)	1
pulmonary embolism	4/70 (5.7%)	4
Ventriculoperitoneal shunt placement.	1/70 (1.4%)	1
Ear and labyrinth disorders
Falling episode/syncopal episode status post fall	1/70 (1.4%)	1
Eye disorders
Left retinal detachment	1/70 (1.4%)	1
Gastrointestinal disorders
Acute inferior wall MI	1/70 (1.4%)	1
Bowel perforation	1/70 (1.4%)	1
Gastroenteritis due to E. coli.	1/70 (1.4%)	1
GI Bleeding	2/70 (2.9%)	2
Nausea	2/70 (2.9%)	2
Perforated sigmoid diverticulum	1/70 (1.4%)	1
vomiting	1/70 (1.4%)	2
General disorders
Acute dehydration	1/70 (1.4%)	1
Coma	1/70 (1.4%)	1
Fatigue	2/70 (2.9%)	2
Flu like symptoms	1/70 (1.4%)	1
Hypertension	1/70 (1.4%)	1
hypotention	1/70 (1.4%)	1
Infections and infestations
Fungal infection (Left lung)	1/70 (1.4%)	1
Upper Resp. tract Infection	1/70 (1.4%)	1
Wound infection	1/70 (1.4%)	1
Investigations
Craniotomy wound w/cerebrospinal fluid leak	2/70 (2.9%)	2
Metabolism and nutrition disorders
Hypoglycemia	1/70 (1.4%)	1
Musculoskeletal and connective tissue disorders
Wound dehisicence of frontal wound	1/70 (1.4%)	1
Nervous system disorders
Seizure	3/70 (4.3%)	3
Psychiatric disorders
Altered mental status	6/70 (8.6%)	7
Steroid-induced psychosis	1/70 (1.4%)	1
Renal and urinary disorders
Acute renal failure	1/70 (1.4%)	1
obstructive uropathy	1/70 (1.4%)	1
Renal failure	1/70 (1.4%)	2
Urinary Tract Infection	1/70 (1.4%)	2
Vascular disorders
Deep vein thrombosis	2/70 (2.9%)	2
Other (Not Including Serious) Adverse Events
	Bevacizumab, Temozolomide, External Beam Radiation
	Affected / at Risk (%)	# Events
Total	14/70 (20%)
Blood and lymphatic system disorders
Hypertension	7/70 (10%)	7
Proteinuria	5/70 (7.1%)	5
General disorders
Fatigue	12/70 (17.1%)	12
Syncope	5/70 (7.1%)	5

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT 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.