Avastin in Combination With Radiation (XRT) & Temozolomide, Followed by Avastin, Temozolomide and Irinotecan for Glioblastoma (GBM) and Gliosarcomas

• Sponsor: Duke University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00597402
• Collaborator: Genentech, Inc. (Industry), Schering-Plough (Industry)
• Enrollment: 125
• Location: 1
• Arm: 1
• Duration (Months): 70
• Patients Per Site Per Month: 1.8

Study Details

Study Description

Brief Summary

Primary objective: To use overall survival to assess the efficacy of the combination of radiation therapy, temozolomide and Avastin followed by Avastin, temozolomide, and irinotecan in the treatment of grade IV malignant glioma patients following surgical resection.

Secondary objective: To determine the progression-free survival following the combination of radiation therapy, temozolomide and Avastin followed by Avastin, temozolomide, and irinotecan.

Exploratory Objective: To explore the relationship between biomarkers and outcome (overall survival and progression-free survival) among patients with grade IV malignant glioma treated with radiation therapy, temozolomide and Avastin followed by Avastin, temozolomide, and irinotecan.

To describe the toxicity of radiation therapy,temozolomide and Avastin followed by Avastin, temozolomide, and irinotecan.

Condition or Disease	Intervention/Treatment	Phase
Glioblastoma; Gliosarcoma; Brain Tumor	Drug: Avastin; Drug: Temozolomide; Radiation: Radiation Therapy (XRT); Drug: Irinotecan	Phase 2

Detailed Description

The standard of care for grade IV gliomas is radiation therapy with daily temozolomide, followed by 6 months of temozolomide. The majority of patients progress and die of their tumor. Many glioma patients are resistant to temozolomide because the tumors have high O(6)-methylguanine-DNA methyltransferase (MGMT), conferring resistance. Irinotecan is synergistic with temozolomide, and the combination may overcome high MGMT. Vascular endothelial growth factor (VEGF) is present on the cell surface and around malignant gliomas. It appears that the presence of vascular endothelial growth factor is a prognostic growth factor with more VEGF expression correlating with a poor prognosis. Monoclonal antibodies to VEGF have inhibited growth of malignant gliomas in a mouse xenograft. Avastin is a humanized monoclonal immunoglobulin G (IGG) 1 antibody that binds to and inhibits the biologic activity of human vascular endothelial growth factor. The combination of Avastin and irinotecan was safe and demonstrated high activity against recurrent malignant gliomas. The combination of Avastin, temozolomide, and irinotecan as the initial therapy may maximize the chance for long-term survival. There are other studies completed or ongoing for newly diagnosed glioblastoma (GBM) patients, including a Radiation Therapy Oncology Group (RTOG) study that added irinotecan to temozolomide following standard radiation therapy and temozolomide, and a University of California, Los Angeles (UCLA) study that added Avastin to standard radiation therapy and temozolomide followed by Avastin and temozolomide.

Study Design

• Study Type: Interventional
• Actual Enrollment: 125 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Avastin in Combination With Radiation and Temozolomide, Followed by Avastin, Temozolomide and Irinotecan for Glioblastoma Multiformes and Gliosarcomas
• Study Start Date: Jul 1, 2007
• Actual Primary Completion Date: Aug 1, 2011
• Actual Study Completion Date: May 1, 2013

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Avastin, radiation, temozolomide, and irinotecan

Drug: Avastin; Avastin will be administered 10 mg/kg every other week beginning a minimum of 28 days after last major surgical procedure, open biopsy, or significant traumatic injury. Following completion of XRT, patients will receive treatment that includes 6 cycles of Avastin, beginning a minimum of 14 days after last XRT.; Other Names: Bevacizumab ; Drug: Temozolomide; Daily temozolomide 75 mg/m2/day for 6.5 weeks of radiation treatment. Following completion of XRT, patients will receive treatment including temozolomide 200 mg/m2/day on the 1st 5 days of each 28-day cycle.; Other Names: Temodar ; Radiation: Radiation Therapy (XRT); Treatment with standard XRT (radiation) for 6.5 weeks.; Drug: Irinotecan; Following completion of XRT, patients will receive 6 cycles of treatment that includes irinotecan. Beginning a minimum of 14 days after last XRT, the irinotecan dose will depend on whether the patient is on enzyme-inducing antiepileptic drugs (EIAED). (EIAED:340 mg/m2 every other week, non-EIAED: 125 mg/m2.); Other Names: CPT-11 Camptosar

Outcome Measures

Primary Outcome Measures

1. 16-month Overall Survival (OS) [16 months]

   Percentage of participants surviving sixteen months from the start of study treatment. OS was defined as the time from the date of study treatment initiation to the date of death due to any cause.

Secondary Outcome Measures

1. 12-month Progression-free Survival (PFS) [12 months]

   Percentage of participants surviving twelve 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.

2. Number of Patients Experiencing a Central Nervous System (CNS) Hemorrhage or a Systemic Hemorrhage [55 months]

   Number of times a CNS hemorrhage or systemic hemorrhage was experienced

3. Number of Patients Experiencing a Grade ≥ 4 Hematologic or Grade ≥ 3 Non-hematologic Toxicity [55 months]

   Number of times a grade ≥ 4 hematologic or grade ≥ 3 non-hematologic toxicity was experienced

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 World Health Organization (WHO) grade IV primary malignant glioma (glioblastoma multiforme or gliosarcoma). Patients have to be within 4 weeks of the last major surgical procedure.

• Age > 18 years.

• An interval of at least 2 weeks and not > 6 weeks between prior major surgical procedure and study enrollment.

• No prior radiotherapy or chemotherapy for a brain tumor

• Karnofsky ≥ 60 percent.

• Hemoglobin ≥ 9.0 g/deciliter (dl), absolute neutrophil count (ANC) ≥ 1,500 cells/ microliter, platelets ≥ 125,000 cells/microliter.

• Serum creatinine ≤ 1.5 mg/dl, serum serum glutamic-oxaloacetic transaminase (SGOT) and bilirubin ≤ 1.5 times upper limit of normal (ULN).

• For patients on corticosteroids, they must be on a stable or decreasing dose for 1 week prior to entry, and the dose should not be escalated over entry dose level, if clinically possible.

• Signed informed consent approved by the Institutional Review Board

• No evidence of > grade 1 central nervous system (CNS) hemorrhage on the baseline MRI or CT scan.

• If sexually active, patients will take contraceptive measures for the duration of treatment as stated in the informed consent.

Exclusion Criteria:

• Pregnancy or breast feeding.

• Co-medication that may interfere with study results; e.g. immuno-suppressive agents other than corticosteroids.

• Active infection requiring intravenous (IV) antibiotics.

• Prior treatment with radiotherapy or chemotherapy for a brain tumor, irrespective of the grade of the tumor.

• Evidence of > grade 1 CNS hemorrhage on baseline MRI on CT scan.

Avastin-Specific Concerns:

Subjects meeting any of the following criteria are ineligible for study entry:

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

• Blood pressure of 150/100 mmHg

• Unstable angina

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

• History of myocardial infarction within 6 months

• History of stroke within 6 months

• Clinically significant peripheral vascular disease

• Evidence of bleeding diathesis

• Coagulopathy (prothrombin time (PT) or partial thromboplastin time (PTT) >1.5x normal or a history of > three grade 2 or greater hemorrhages)

• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to first Avastin infusion during XRT/Temodar or anticipation of need for major surgical procedure during the course of the study

• Minor surgical procedures, fine needle aspirations or core biopsies within 7 days prior to first Avastin infusion during XRT/Temodar

• Pregnant (positive pregnancy test) or lactating

• Urine protein >1.0 + at screening

• History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to first Avastin infusion during XRT/Temodar

• Serious, non-healing wound, ulcer, or bone fractures.

• Inability to comply with study and/or follow-up procedures.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Duke University Health System	Durham	North Carolina	United States	27710

Sponsors and Collaborators

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

Investigators

• Principal Investigator: Annick Desjardins, MD, FRCPC, 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: NCT00597402
• Other Study ID Numbers: Pro00000458
• First Posted: Jan 18, 2008
• Last Update Posted: May 7, 2014
• Last Verified: Apr 1, 2014

• Keywords provided by Duke University: Avastin; Bevacizumab; Temozolomide; Temodar; Irinotecan; Camptosar; GBM; Glioblastoma Multiforme; Gliosarcoma; Brain tumor; Glioma; New GBM; Newly diagnosed GBM or gliosarcoma malignant brain tumor
• Additional relevant MeSH terms: Glioblastoma; Brain Neoplasms; Gliosarcoma; Bevacizumab; Irinotecan; Temozolomide

Study Results

Participant Flow

Arm/Group Title	Avastin, Radiation, Temozolomide, and Irinotecan
Arm/Group Description	Treatment with standard XRT (radiation) and daily temozolomide 75 mg/m2/day for 6.5 weeks of XRT. Avastin will be administered 10 mg/kg every other week beginning a minimum of 28 days after last major surgical procedure, open biopsy, or significant traumatic injury. Following completion of XRT, patients will receive 6 cycles of Avastin, temozolomide, and irinotecan. Beginning a minimum of 14 days after last XRT, Avastin at 10 mg/kg with irinotecan every other week; temozolomide will be given at 200 mg/m2/day on the 1st 5 days of each 28-day cycle. The irinotecan dose will depend on whether the patient is taking enzyme-inducing antiepileptic drugs (EIAED). (EIAED:340 mg/m2 every other week, non-EIAED:125 mg/m2.)
Period Title: Overall Study
STARTED	125
COMPLETED	125
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Avastin, Radiation, Temozolomide, and Irinotecan
Arm/Group Description	Treatment with standard XRT (radiation) and daily temozolomide 75 mg/m2/day for 6.5 weeks of XRT. Avastin will be administered 10 mg/kg every other week beginning a minimum of 28 days after last major surgical procedure, open biopsy, or significant traumatic injury. Following completion of XRT, patients will receive 6 cycles of Avastin, temozolomide, and irinotecan. Beginning a minimum of 14 days after last XRT, Avastin at 10 mg/kg with irinotecan every other week; temozolomide will be given at 200 mg/m2/day on the 1st 5 days of each 28-day cycle. The irinotecan dose will depend on whether the patient is taking enzyme-inducing antiepileptic drugs (EIAED). (EIAED:340 mg/m2 every other week, non-EIAED:125 mg/m2.)
Overall Participants	125
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54.6 (12.5)
Sex: Female, Male (Count of Participants)
Female	51 40.8%
Male	74 59.2%

Outcome Measures

1. Primary Outcome

Title	16-month Overall Survival (OS)
Description	Percentage of participants surviving sixteen months from the start of study treatment. OS was defined as the time from the date of study treatment initiation to the date of death due to any cause.
Time Frame	16 months

Outcome Measure Data

Analysis Population Description

Intent to treat

Arm/Group Title	Avastin, Radiation, Temozolomide, and Irinotecan
Arm/Group Description	Treatment with standard XRT (radiation) and daily temozolomide 75 mg/m2/day for 6.5 weeks of XRT. Avastin will be administered 10 mg/kg every other week beginning a minimum of 28 days after last major surgical procedure, open biopsy, or significant traumatic injury. Following completion of XRT, patients will receive 6 cycles of Avastin, temozolomide, and irinotecan. Beginning a minimum of 14 days after last XRT, Avastin at 10 mg/kg with irinotecan every other week; temozolomide will be given at 200 mg/m2/day on the 1st 5 days of each 28-day cycle. The irinotecan dose will depend on whether the patient is taking enzyme-inducing antiepileptic drugs (EIAED). (EIAED:340 mg/m2 every other week, non-EIAED:125 mg/m2.)
Measure Participants	125
Number (95% Confidence Interval) [percentage of participants]	64.8 51.8%

2. Secondary Outcome

Title	12-month Progression-free Survival (PFS)
Description	Percentage of participants surviving twelve 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.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Avastin, Radiation, Temozolomide, and Irinotecan
Arm/Group Description	Treatment with standard XRT (radiation) and daily temozolomide 75 mg/m2/day for 6.5 weeks of XRT. Avastin will be administered 10 mg/kg every other week beginning a minimum of 28 days after last major surgical procedure, open biopsy, or significant traumatic injury. Following completion of XRT, patients will receive 6 cycles of Avastin, temozolomide, and irinotecan. Beginning a minimum of 14 days after last XRT, Avastin at 10 mg/kg with irinotecan every other week; temozolomide will be given at 200 mg/m2/day on the 1st 5 days of each 28-day cycle. The irinotecan dose will depend on whether the patient is taking enzyme-inducing antiepileptic drugs (EIAED). (EIAED:340 mg/m2 every other week, non-EIAED:125 mg/m2.)
Measure Participants	125
Number (95% Confidence Interval) [percentage of participants]	63.2 50.6%

3. Secondary Outcome

Title	Number of Patients Experiencing a Central Nervous System (CNS) Hemorrhage or a Systemic Hemorrhage
Description	Number of times a CNS hemorrhage or systemic hemorrhage was experienced
Time Frame	55 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Avastin, Radiation, Temozolomide, and Irinotecan
Arm/Group Description	Treatment with standard XRT (radiation) and daily temozolomide 75 mg/m2/day for 6.5 weeks of XRT. Avastin will be administered 10 mg/kg every other week beginning a minimum of 28 days after last major surgical procedure, open biopsy, or significant traumatic injury. Following completion of XRT, patients will receive 6 cycles of Avastin, temozolomide, and irinotecan. Beginning a minimum of 14 days after last XRT, Avastin at 10 mg/kg with irinotecan every other week; temozolomide will be given at 200 mg/m2/day on the 1st 5 days of each 28-day cycle. The irinotecan dose will depend on whether the patient is taking enzyme-inducing antiepileptic drugs (EIAED). (EIAED:340 mg/m2 every other week, non-EIAED:125 mg/m2.)
Measure Participants	125
Gr.2 Central Nervous System (CNS) Hemorrhage	1 0.8%
Gr.3 Central Nervous System (CNS) Hemorrhage	0 0%
Gr.4 Central Nervous System (CNS) Hemorrhage	1 0.8%
Gr.5 Central Nervous System (CNS) Hemorrhage	0 0%
Gr.2 Systemic Hemorrhage	1 0.8%
Gr.3 Systemic Hemorrhage	0 0%
Gr.4 Systemic Hemorrhage	0 0%
Gr.5 Systemic Hemorrhage	0 0%

4. Secondary Outcome

Title	Number of Patients Experiencing a Grade ≥ 4 Hematologic or Grade ≥ 3 Non-hematologic Toxicity
Description	Number of times a grade ≥ 4 hematologic or grade ≥ 3 non-hematologic toxicity was experienced
Time Frame	55 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Avastin, Radiation, Temozolomide, and Irinotecan
Arm/Group Description	Treatment with standard XRT (radiation) and daily temozolomide 75 mg/m2/day for 6.5 weeks of XRT. Avastin will be administered 10 mg/kg every other week beginning a minimum of 28 days after last major surgical procedure, open biopsy, or significant traumatic injury. Following completion of XRT, patients will receive 6 cycles of Avastin, temozolomide, and irinotecan. Beginning a minimum of 14 days after last XRT, Avastin at 10 mg/kg with irinotecan every other week; temozolomide will be given at 200 mg/m2/day on the 1st 5 days of each 28-day cycle. The irinotecan dose will depend on whether the patient is taking enzyme-inducing antiepileptic drugs (EIAED). (EIAED:340 mg/m2 every other week, non-EIAED:125 mg/m2.)
Measure Participants	125
Grade ≥ 4 Hematologic Toxicities	20 16%
Grade ≥3 Non-hematologic Toxicities	49 39.2%

Adverse Events

Time Frame	55 months
Adverse Event Reporting Description	Adverse events collected using Common Terminology Criteria for Adverse Events (CTCAE) v.3.0 and converted to v.4.0 for ClinicalTrials.gov entry.
Arm/Group Title	Avastin, Radiation, Temozolomide, and Irinotecan
Arm/Group Description	Treatment with standard XRT (radiation) and daily temozolomide 75 mg/m2/day for 6.5 weeks of XRT. Avastin will be administered 10 mg/kg every other week beginning a minimum of 28 days after last major surgical procedure, open biopsy, or significant traumatic injury. Following completion of XRT, patients will receive 6 cycles of Avastin, temozolomide, and irinotecan. Beginning a minimum of 14 days after last XRT, Avastin at 10 mg/kg with irinotecan every other week; temozolomide will be given at 200 mg/m2/day on the 1st 5 days of each 28-day cycle. The irinotecan dose will depend on whether the patient is taking enzyme-inducing antiepileptic drugs (EIAED). (EIAED:340 mg/m2 every other week, non-EIAED:125 mg/m2.)
All Cause Mortality
	Avastin, Radiation, Temozolomide, and Irinotecan
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Avastin, Radiation, Temozolomide, and Irinotecan
	Affected / at Risk (%)	# Events
Total	35/125 (28%)
Blood and lymphatic system disorders
Anemia	4/125 (3.2%)
Cardiac disorders
Atrial fibrillation	1/125 (0.8%)
Gastrointestinal disorders
Colitis	1/125 (0.8%)
Gastrointestinal disorders - Other, specify	1/125 (0.8%)
Hemorrhoids	1/125 (0.8%)
Upper gastrointestinal hemorrhage	1/125 (0.8%)
General disorders
Death NOS	2/125 (1.6%)
Fatigue	1/125 (0.8%)
Sudden death NOS	1/125 (0.8%)
Infections and infestations
Bone infection	1/125 (0.8%)
Infections and infestations - Other, specify	1/125 (0.8%)
Infections and infestations - Other, specify: Infecti	2/125 (1.6%)
Lung infection	3/125 (2.4%)
Skin infection	1/125 (0.8%)
Urinary tract infection	2/125 (1.6%)
Investigations
Neutrophil count decreased	3/125 (2.4%)
Platelet count decreased	4/125 (3.2%)
White blood cell decreased	3/125 (2.4%)
Metabolism and nutrition disorders
Dehydration	1/125 (0.8%)
Hyperglycemia	1/125 (0.8%)
Hyponatremia	1/125 (0.8%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Treatment related secondary malignancy	1/125 (0.8%)
Nervous system disorders
Cerebrospinal fluid leakage	1/125 (0.8%)
Cognitive disturbance	1/125 (0.8%)
Headache	2/125 (1.6%)
Intracranial hemorrhage	2/125 (1.6%)
Peripheral motor neuropathy	1/125 (0.8%)
Seizure	13/125 (10.4%)
Psychiatric disorders
Confusion	5/125 (4%)
Psychosis	1/125 (0.8%)
Vascular disorders
Thromboembolic event	7/125 (5.6%)
Other (Not Including Serious) Adverse Events
	Avastin, Radiation, Temozolomide, and Irinotecan
	Affected / at Risk (%)	# Events
Total	45/125 (36%)
General disorders
Fatigue	10/125 (8%)
Investigations
Neutrophil count decreased	25/125 (20%)
Platelet count decreased	23/125 (18.4%)

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.