Bevacizumab in Combination With Metronomic Temozolomide for Recurrent Malignant Glioma

• Sponsor: Duke University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00501891
• Collaborator: Genentech, Inc. (Industry), Schering-Plough (Industry)
• Enrollment: 32
• Location: 1
• Arm: 1
• Duration (Months): 28.1
• Patients Per Site Per Month: 1.1

Study Details

Study Description

Brief Summary

This is a phase II study of the combination of Avastin and metronomic temozolomide in recurrent malignant glioma patients. The primary objective will be to determine the efficacy of Avastin (bevacizumab) and metronomic temozolomide in malignant glioma patients. The secondary objective will be to determine the safety of Avastin, 10 mg/kg every other week, in combination with metronomic temozolomide in terms of progression-free survival.

Condition or Disease	Intervention/Treatment	Phase
Glioblastoma Multiforme	Drug: Bevacizumab; Drug: Metronomic Temozolomide	Phase 2

Detailed Description

This is a phase II trial of the combination of Avastin and metronomic temozolomide in recurrent WHO grade IV malignant glioma patients. Patients will receive up to 12 cycles of Avastin and temozolomide and cycles are continuous 28 days. Patients will receive daily temozolomide at a dose of 50mg/m2 and will receive Avastin every other week at a dose of 10mg/kg. Patients will be required to have a baseline MRI within 2 weeks of starting treatment and a repeat MRI every 8 weeks. A total of 32 patients will be enrolled at Duke.

Patients with recurrent malignant gliomas have a very poor prognosis, so new therapies are needed. Given the activity of metronomic temozolomide and the safety and activity of Avastin against malignant glioma, it is reasonable to study the combination in recurrent malignant glioma patients.

Study Design

• Study Type: Interventional
• Actual Enrollment: 32 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Bevacizumab in Combination With Metronomic Temozolomide for Recurrent Malignant Glioma
• Study Start Date: Jul 1, 2007
• Actual Primary Completion Date: Dec 1, 2007
• Actual Study Completion Date: Nov 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Bevacizumab and Metronomic Temozolomide Patients will receive up to 12 cycles of bevacizumab (Avastin) and metronomic temozolomide (Temodar), and each cycle is 28 days. Bevacizumab will be administered at 10 mg/kg every other week beginning a minimum of 7 days after a biopsy or 28 days after a craniotomy. Temozolomide will be dosed at 50 mg/m2 daily in a 28-day cycle.	Drug: Bevacizumab; Bevacizumab administered intravenously 10mg/kg every other week.; Other Names: Avastin ; Drug: Metronomic Temozolomide; Temozolomide 50mg/m2 given orally on a daily basis.; Other Names: Temodar

Outcome Measures

Primary Outcome Measures

1. 6-Month Progression-free Survival [6 months]

   Percentage of participants surviving six months from the start of study treatment without progression of disease. PFS was defined as the time from the date of study treatment initiation to the date of the first documented progression according to the Macdonald criteria, or to death due to any cause. [Optional: Macdonald criteria are standard criteria in neuro-oncology. Tumor assessment was made according to the adapted MacDonald criteria based on the combined evaluation of: 1) assessment of the MRI scan for measurable, evaluable, and new lesions (made by the independent external expert too), 2) overall assessment of neurological performance (made by the investigator), 3) concomitant steroid use (as reported by the investigator).]

Secondary Outcome Measures

1. Response Rate [27 months]

   The number of participants with complete or partial response as determined by a modification of the Macdonald criteria. Complete response was defined as complete disappearance on MR/CT of all enhancing tumor and mass effect, off all corticosteroids (or receiving only adrenal replacement doses), accompanied by a stable or improving neurologic examination, and maintained for at least 4 weeks. Partial Response was defined as greater than or equal to 50% reduction in tumor size on MR/CT by bi-dimensional measurement, on a stable or decreasing dose of corticosteroids, accompanied by a stable or improving neurologic examination, and maintained for at least 4 weeks.

2. Incidence and Severity of CNS Hemorrhage and Systemic Hemorrhage [27 months]

   Number of participants experiencing a Central Nervous System (CNS) hemorrhage or systemic hemorrhage

3. Incidence of Grade ≥ 4 Hematologic or Grade ≥ 3 Non-hematologic Toxicity [27 months]

   Number of participants experiencing a grade ≥4 hematologic or grade ≥3 non-hematologic toxicity

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 WHO grade IV primary malignant glioma

• Karnofsy Performance Status (KPS) >/= 60%

• Evidence of measurable primary CNS neoplasm on contrast-enhanced MRI.

• An interval of at least 4 weeks between prior surgical resection or 1 week from a biopsy and enrollment on this protocol

• An interval of at least 4 weeks from the end of prior radiotherapy or one week from the end of a cycle of chemotherapy and enrollment on this protocol.

• No evidence of CNS hemorrhage on the baseline MRI or CT scans

Exclusion Criteria:

• Life expectancy < 8 weeks

• Pregnancy or breast feeding

• Progression to metronomic temozolomide, defined as tumor progression while taking daily temozolomide or progression within 4 weeks of stopping metronomic temozolomide

• Inadequately controlled hypertension (defined as systolic blood pressure >150 and/or diastolic blood pressure > 100 mmHg on antihypertensive medications)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Duke University Medical Center (Brain Tumor Center)	Durham	North Carolina	United States	27710

Sponsors and Collaborators

• Duke University
• Genentech, Inc.
• Schering-Plough

Investigators

• Principal Investigator: Annick Desjardins, MD, Duke Health

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• The Preston Robert Tisch Brain Tumor Center at Duke

Publications

None provided.

• Responsible Party: Duke University
• ClinicalTrials.gov Identifier: NCT00501891
• Other Study ID Numbers: Pro00000404; AVF3821s; P04860
• First Posted: Jul 16, 2007
• Last Update Posted: May 27, 2013
• Last Verified: Mar 1, 2013

• Keywords provided by Duke University: Glioblastoma Multiforme; Brain and Central Nervous System Tumors; Recurrent Malignant Glioma; Recurrent Glioblastoma Multiforme; Avastin; Bevacizumab; Temodar; Temozolomide
• Additional relevant MeSH terms: Glioblastoma; Glioma; Bevacizumab; Temozolomide

Study Results

Participant Flow

Arm/Group Title	Bevacizumab and Temozolomide
Arm/Group Description	Patients will receive up to 12 cycles of Avastin and temozolomide, and each cycle is 28 days. Avastin will be administered at 10 mg/kg every other week beginning a minimum of 7 days after a biopsy or 28 days after a craniotomy. Temozolomide will be dosed at 50 mg/m2 daily in a 28-day cycle.
Period Title: Overall Study
STARTED	32
COMPLETED	32
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Bevacizumab and Temozolomide
Arm/Group Description	Patients will receive up to 12 cycles of Avastin and temozolomide, and each cycle is 28 days. Avastin will be administered at 10 mg/kg every other week beginning a minimum of 7 days after a biopsy or 28 days after a craniotomy. Temozolomide will be dosed at 50 mg/m2 daily in a 28-day cycle.
Overall Participants	32
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54.4 (12.8)
Sex: Female, Male (Count of Participants)
Female	13 40.6%
Male	19 59.4%

Outcome Measures

1. Primary Outcome

Title	6-Month Progression-free Survival
Description	Percentage of participants surviving six months from the start of study treatment without progression of disease. PFS was defined as the time from the date of study treatment initiation to the date of the first documented progression according to the Macdonald criteria, or to death due to any cause. [Optional: Macdonald criteria are standard criteria in neuro-oncology. Tumor assessment was made according to the adapted MacDonald criteria based on the combined evaluation of: 1) assessment of the MRI scan for measurable, evaluable, and new lesions (made by the independent external expert too), 2) overall assessment of neurological performance (made by the investigator), 3) concomitant steroid use (as reported by the investigator).]
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Intent to treat

Arm/Group Title	Bevacizumab and Metronomic Temozolomide
Arm/Group Description	Patients will receive up to 12 cycles of Avastin and temozolomide, and each cycle is 28 days. Avastin will be administered at 10 mg/kg every other week beginning a minimum of 7 days after a biopsy or 28 days after a craniotomy. Temozolomide will be dosed at 50 mg/m2 daily in a 28-day cycle.
Measure Participants	32
Number (95% Confidence Interval) [percentage of participants]	18.8 58.8%

2. Secondary Outcome

Title	Response Rate
Description	The number of participants with complete or partial response as determined by a modification of the Macdonald criteria. Complete response was defined as complete disappearance on MR/CT of all enhancing tumor and mass effect, off all corticosteroids (or receiving only adrenal replacement doses), accompanied by a stable or improving neurologic examination, and maintained for at least 4 weeks. Partial Response was defined as greater than or equal to 50% reduction in tumor size on MR/CT by bi-dimensional measurement, on a stable or decreasing dose of corticosteroids, accompanied by a stable or improving neurologic examination, and maintained for at least 4 weeks.
Time Frame	27 months

Outcome Measure Data

Analysis Population Description

Intent to treat

Arm/Group Title	Bevacizumab and Metronomic Temozolomide
Arm/Group Description	Patients will receive up to 12 cycles of Avastin and temozolomide, and each cycle is 28 days. Avastin will be administered at 10 mg/kg every other week beginning a minimum of 7 days after a biopsy or 28 days after a craniotomy. Temozolomide will be dosed at 50 mg/m2 daily in a 28-day cycle.
Measure Participants	32
Number [Number of participants]	9 28.1%

3. Secondary Outcome

Title	Incidence and Severity of CNS Hemorrhage and Systemic Hemorrhage
Description	Number of participants experiencing a Central Nervous System (CNS) hemorrhage or systemic hemorrhage
Time Frame	27 months

Outcome Measure Data

Analysis Population Description

Intent to treat

Arm/Group Title	Bevacizumab and Metronomic Temozolomide
Arm/Group Description	Patients will receive up to 12 cycles of Avastin and temozolomide, and each cycle is 28 days. Avastin will be administered at 10 mg/kg every other week beginning a minimum of 7 days after a biopsy or 28 days after a craniotomy. Temozolomide will be dosed at 50 mg/m2 daily in a 28-day cycle.
Measure Participants	32
CNS Hemorrhage	0 0%
Systemic Hemorrhage	0 0%

4. Secondary Outcome

Title	Incidence of Grade ≥ 4 Hematologic or Grade ≥ 3 Non-hematologic Toxicity
Description	Number of participants experiencing a grade ≥4 hematologic or grade ≥3 non-hematologic toxicity
Time Frame	27 months

Outcome Measure Data

Analysis Population Description

Intent to treat

Arm/Group Title	Bevacizumab and Metromonic Temozolomide
Arm/Group Description	Patients will receive up to 12 cycles of Avastin and temozolomide, and each cycle is 28 days. Avastin will be administered at 10 mg/kg every other week beginning a minimum of 7 days after a biopsy or 28 days after a craniotomy. Temozolomide will be dosed at 50 mg/m2 daily in a 28-day cycle.
Measure Participants	32
Grade ≥ 4 hematologic toxicities	0 0%
Grade ≥ 3 non-hematologic toxicities	14 43.8%

Adverse Events

Time Frame	27 months
Adverse Event Reporting Description	The adverse events were gather in Common Terminology Criteria for Adverse Events (CTCAE) v.3.0, and have been converted to v.4.0 for entry into ClinicalTrials.gov.
Arm/Group Title	Bevacizumab and Temozolomide
Arm/Group Description	Patients will receive up to 12 cycles of Avastin and temozolomide, and each cycle is 28 days. Avastin will be administered at 10 mg/kg every other week beginning a minimum of 7 days after a biopsy or 28 days after a craniotomy. Temozolomide will be dosed at 50 mg/m2 daily in a 28-day cycle.
All Cause Mortality
	Bevacizumab and Temozolomide
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Bevacizumab and Temozolomide
	Affected / at Risk (%)	# Events
Total	8/32 (25%)
Gastrointestinal disorders
Colitis	1/32 (3.1%)
Diarrhea	1/32 (3.1%)
Hemorrhoids	1/32 (3.1%)
Pancreatitis	1/32 (3.1%)
General disorders
Death NOS	3/32 (9.4%)
Infections and infestations
Lung infection	1/32 (3.1%)
Metabolism and nutrition disorders
Dehydration	1/32 (3.1%)
Hyperglycemia	1/32 (3.1%)
Musculoskeletal and connective tissue disorders
Generalized muscle weakness	1/32 (3.1%)
Nervous system disorders
Cognitive disturbance	1/32 (3.1%)
Dysphasia	1/32 (3.1%)
Seizure	1/32 (3.1%)
Other (Not Including Serious) Adverse Events
	Bevacizumab and Temozolomide
	Affected / at Risk (%)	# Events
Total	15/32 (46.9%)
Eye disorders
Blurred vision	6/32 (18.8%)
Gastrointestinal disorders
Nausea	3/32 (9.4%)
General disorders
Fatigue	6/32 (18.8%)
Nervous system disorders
Ataxia	5/32 (15.6%)
Cognitive disturbance	2/32 (6.3%)
Depressed level of consciousness	4/32 (12.5%)
Dysphasia	3/32 (9.4%)
Memory impairment	6/32 (18.8%)
Peripheral motor neuropathy	6/32 (18.8%)
Psychiatric disorders
Confusion	3/32 (9.4%)
Insomnia	2/32 (6.3%)
Reproductive system and breast disorders
Sexual dysfunction, NOS	2/32 (6.3%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	3/32 (9.4%)
Skin and subcutaneous tissue disorders
Rash maculo-papular	2/32 (6.3%)
Vascular disorders
Hypertension	2/32 (6.3%)

Limitations/Caveats

[Not Specified]

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.