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Avastin/Radiation (XRT)/Temozolomide (Temodar) Followed by Avastin/Temodar/Topotecan for Glioblastoma

Primary Purpose

Malignant Glioma, Glioblastoma, Gliosarcoma

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Bevacizumab
Temozolomide
Radiation Therapy (XRT)
Topotecan
Sponsored by
Duke University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Malignant Glioma focused on measuring malignant glioma, glioblastoma, gliosarcoma, Avastin, bevacizumab, Topotecan, Hycamtin, Temozolomide, Temodar, Pro00019960, Vredenburgh, Duke, Desjardins

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patients must have histologically confirmed diagnosis of WHO grade IV primary malignant glioma (glioblastoma multiforme or gliosarcoma). Patients have to be within 6 weeks of the last major surgical procedure.
  • Age > or = to 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 > or = to 60%.
  • Hemoglobin ≥ 9.0 g/dl, absolute neutrophil count (ANC) ≥ 1,500 cells/microliter, platelets ≥ 125,000 cells/microliter.
  • Serum creatinine ≤ 1.5 mg/dl, serum glutamic oxaloacetic transaminase (SGOT) and bilirubin ≤ 1.5 times upper limit of normal.
  • Signed informed consent approved by the Institutional Review Board
  • If sexually active, patients must agree to use appropriate contraceptive measures for the duration of the study and for 6 months afterwards 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 IV antibiotics.
  • Prior treatment with radiotherapy or chemotherapy for a brain tumor, irrespective of the grade of the tumor.
  • Evidence of > grade 1 central nervous system (CNS) hemorrhage on baseline MRI on CT scan.

Avastin-specific Exclusion Criteria:

  • Inadequately controlled hypertension (defined as systolic blood pressure > 150 and/or diastolic blood pressure > 100 mmHg)
  • Prior history of hypertensive crisis or hypertensive encephalopathy
  • New York Heart Association (NYHA) Grade II or greater congestive heart failure
  • History of myocardial infarction or unstable angina within 6 months prior to study enrollment
  • History of stroke or transient ischemic attack within 6 months prior to study enrollment
  • Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to study enrollment
  • History of hemoptysis (≥ ½ teaspoon of bright red blood per episode) within 1 month prior to study enrollment
  • Evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic anticoagulation)
  • Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study enrollment or anticipation of need for major surgical procedure during the course of the study
  • Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to study enrollment
  • History of abdominal fistula, gastrointestinal perforation within 6 months prior to study enrollment
  • Serious, non-healing wound, active ulcer, or untreated bone fracture
  • Proteinuria at screening as demonstrated by either urine protein:creatinine (UPC) ratio ≥ 1.0 at screening OR urine dipstick for proteinuria ≥ 2+ (patients discovered to have ≥2+ proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate ≤ 1g of protein in 24 hours to be eligible).
  • Known hypersensitivity to any component of Avastin
  • Pregnant (positive pregnancy test) or lactation. Use of effective means of contraception (men and women) in subjects of child-bearing potential

Sites / Locations

  • The Preston Robert Tisch Brain Tumor Center at Duke

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Bevacizumab, XRT, Temozolomide, Topotecan

Arm Description

Patients are treated with standard radiation therapy and daily temozolomide at 75 mg/ m2 daily for 6.5 weeks of radiation. Following completion of radiation therapy, patients have a MRI and, if there is no evidence of disease progression, patients receive 12 cycles of Avastin, temozolomide, and topotecan. Beginning a minimum of 14 days after the last radiation treatment, the Avastin is dosed at 10 mg/kg every other week; temozolomide is given at 150 mg/m2 daily the first 5 days in combination with topotecan on days 2 through 6 at 1.5 mg/ m2 for patient not taking EIAEDs and 2.0 mg/ m2 for patients taking EIAEDs on days 2-6 of each 28-day.

Outcomes

Primary Outcome Measures

6-month Progression-free Survival
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.

Secondary Outcome Measures

One and Two Year Overall Survival
Time in months from the start of study treatment to date of death due to any cause. Patients alive as of the last follow-up had OS censored at the last follow-up date.
Median Overall Survival
OS was defined as time in months from the start of study treatment to date of death due to any cause. Patients alive as of the last follow-up had OS censored at the last follow-up date. Median OS was estimated using a Kaplan-Meier curve.
Number of Patients Experiencing a Central Nervous System (CNS) Hemorrhage or a Systemic Hemorrhage
Number of times a CNS hemorrhage or systemic hemorrhage was experienced
Number of Patients Experiencing a Greater Than or Equal to Grade 4 Hematologic or a Greater Than or Equal to Grade 3 Non-hematologic Toxicity
Number of times a grade ≥4 hematologic or grade ≥3 non-hematologic toxicity was experienced
Median Progression-free Survival
PFS was defined as time in months from the start of study treatment to the date of first progression according to Macdonald criteria, or to death due to any cause. Patients alive who had not progressed as of the last follow-up had PFS censored at the last follow-up date. Median PFS was estimated using a Kaplan-Meier curve.

Full Information

First Posted
October 28, 2009
Last Updated
March 29, 2022
Sponsor
Duke University
Collaborators
Genentech, Inc., GlaxoSmithKline
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1. Study Identification

Unique Protocol Identification Number
NCT01004874
Brief Title
Avastin/Radiation (XRT)/Temozolomide (Temodar) Followed by Avastin/Temodar/Topotecan for Glioblastoma
Official Title
Avastin in Combination With Radiation and Temozolomide Followed by Avastin, Temozolomide, and Topotecan for Glioblastoma Multiformes and Gliosarcomas
Study Type
Interventional

2. Study Status

Record Verification Date
March 2022
Overall Recruitment Status
Completed
Study Start Date
December 30, 2009 (Actual)
Primary Completion Date
July 2012 (Actual)
Study Completion Date
November 2, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Duke University
Collaborators
Genentech, Inc., GlaxoSmithKline

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
This is a phase II study of the combination of radiation therapy, temozolomide and Avastin followed by Avastin, temozolomide, and topotecan in grade IV malignant glioma patients.
Detailed Description
The primary objective of this study is to use 6-month progression-free survival to assess the efficacy of the combination of radiation therapy, temozolomide and Avastin followed by Avastin, temozolomide, and topotecan in the treatment of grade IV malignant glioma patients following surgical resection. Secondary objectives are to determine the overall survival following the combination of radiation therapy, temozolomide and Avastin followed by Avastin, temozolomide, and topotecan and to describe the toxicity of radiation therapy, temozolomide and Avastin followed by Avastin, temozolomide, and topotecan. The study will have survival and toxicity endpoints. Patients will be treated with standard radiation therapy and daily temozolomide for 6 and a half weeks of radiation. Avastin will be administered every other week beginning a minimum of 28 days after the last major surgical procedure, open biopsy, or significant traumatic injury. Following completion of radiation therapy, patients will have a MRI and if there is no evidence of disease progression, patients will receive 12 cycles of Avastin, temozolomide, and topotecan (beginning a minimum of 14 days after the last radiation treatment). Subjects will be identified by the investigator as those patients who have newly diagnosed grade 4 malignant glioma (glioblastoma multiforme or gliosarcoma), and be within 6 weeks of the last major surgical procedure, craniotomy, open biopsy, or stereotactic biopsy. Fifty (50) patients will initially be accrued to the study and the overall efficacy of the treatment regimen assessed. Analyses will be conducted within subgroups defined by methylation status. Early side effects of radiation that may start during radiation include hair loss, scalp redness, inflammation of the ear canals, and fatigue. There is a small chance of long-term effects from radiation, occurring after months or years after completion. These may include worsening of mental function, hearing, vision, strength and coordination. In initial Phase I and II clinical trials, four potential Avastin-associated safety signals were identified: hypertension, proteinuria, thromboembolic events, and hemorrhage. Temozolomide has been well tolerated by both adults and children with the most common toxicity being mild myelosuppression. Other, less likely, potential toxicities include nausea and vomiting, constipation, headache, alopecia, rash, burning sensation of skin, esophagitis, pain, diarrhea, lethargy, and hepatotoxicity. With topotecan, reversible myelosuppression with leukopenia and thrombocytopenia is dose limiting. Nausea and vomiting, as well as diarrhea and alopecia, are frequent. Moderate fatigue, transient elevation of hepatic transaminase levels, stomatitis, anemia, fever, mucositis, flu-like symptoms, and rash have been reported.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Malignant Glioma, Glioblastoma, Gliosarcoma
Keywords
malignant glioma, glioblastoma, gliosarcoma, Avastin, bevacizumab, Topotecan, Hycamtin, Temozolomide, Temodar, Pro00019960, Vredenburgh, Duke, Desjardins

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
80 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Bevacizumab, XRT, Temozolomide, Topotecan
Arm Type
Experimental
Arm Description
Patients are treated with standard radiation therapy and daily temozolomide at 75 mg/ m2 daily for 6.5 weeks of radiation. Following completion of radiation therapy, patients have a MRI and, if there is no evidence of disease progression, patients receive 12 cycles of Avastin, temozolomide, and topotecan. Beginning a minimum of 14 days after the last radiation treatment, the Avastin is dosed at 10 mg/kg every other week; temozolomide is given at 150 mg/m2 daily the first 5 days in combination with topotecan on days 2 through 6 at 1.5 mg/ m2 for patient not taking EIAEDs and 2.0 mg/ m2 for patients taking EIAEDs on days 2-6 of each 28-day.
Intervention Type
Drug
Intervention Name(s)
Bevacizumab
Other Intervention Name(s)
Avastin
Intervention Description
Bevacizumab (Avastin) at 10 mg/kg every other week during standard radiation therapy (XRT). Following XRT, bevacizumab will remain at 10 mg/kg every other week.
Intervention Type
Drug
Intervention Name(s)
Temozolomide
Other Intervention Name(s)
Temodar
Intervention Description
Daily temozolomide at 75 mg/ m2 daily for 6.5 weeks of radiation therapy (XRT). Following XRT, temozolomide will be dosed at 150 mg/m2 daily the first 5 days of each 28-day cycle.
Intervention Type
Radiation
Intervention Name(s)
Radiation Therapy (XRT)
Intervention Description
Standard radiation therapy for approximately 6.5 weeks
Intervention Type
Drug
Intervention Name(s)
Topotecan
Other Intervention Name(s)
Hycamtin
Intervention Description
Following standard radiation therapy, patients will receive topotecan on days 2 through 6 of each 28-day cycle at a dose of 1.5 mg/m2 for patients not taking enzyme-inducing anti-epileptic drugs (EIAEDs) and 2.0 mg/m2 for patients taking EIAEDs.
Primary Outcome Measure Information:
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.
Time Frame
6 months
Secondary Outcome Measure Information:
Title
One and Two Year Overall Survival
Description
Time in months from the start of study treatment to date of death due to any cause. Patients alive as of the last follow-up had OS censored at the last follow-up date.
Time Frame
One year and two years
Title
Median Overall Survival
Description
OS was defined as time in months from the start of study treatment to date of death due to any cause. Patients alive as of the last follow-up had OS censored at the last follow-up date. Median OS was estimated using a Kaplan-Meier curve.
Time Frame
27 months
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
27 months
Title
Number of Patients Experiencing a Greater Than or Equal to Grade 4 Hematologic or a Greater Than or Equal to Grade 3 Non-hematologic Toxicity
Description
Number of times a grade ≥4 hematologic or grade ≥3 non-hematologic toxicity was experienced
Time Frame
27 months
Title
Median Progression-free Survival
Description
PFS was defined as time in months from the start of study treatment to the date of first progression according to Macdonald criteria, or to death due to any cause. Patients alive who had not progressed as of the last follow-up had PFS censored at the last follow-up date. Median PFS was estimated using a Kaplan-Meier curve.
Time Frame
27 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients must have histologically confirmed diagnosis of WHO grade IV primary malignant glioma (glioblastoma multiforme or gliosarcoma). Patients have to be within 6 weeks of the last major surgical procedure. Age > or = to 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 > or = to 60%. Hemoglobin ≥ 9.0 g/dl, absolute neutrophil count (ANC) ≥ 1,500 cells/microliter, platelets ≥ 125,000 cells/microliter. Serum creatinine ≤ 1.5 mg/dl, serum glutamic oxaloacetic transaminase (SGOT) and bilirubin ≤ 1.5 times upper limit of normal. Signed informed consent approved by the Institutional Review Board If sexually active, patients must agree to use appropriate contraceptive measures for the duration of the study and for 6 months afterwards 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 IV antibiotics. Prior treatment with radiotherapy or chemotherapy for a brain tumor, irrespective of the grade of the tumor. Evidence of > grade 1 central nervous system (CNS) hemorrhage on baseline MRI on CT scan. Avastin-specific Exclusion Criteria: Inadequately controlled hypertension (defined as systolic blood pressure > 150 and/or diastolic blood pressure > 100 mmHg) Prior history of hypertensive crisis or hypertensive encephalopathy New York Heart Association (NYHA) Grade II or greater congestive heart failure History of myocardial infarction or unstable angina within 6 months prior to study enrollment History of stroke or transient ischemic attack within 6 months prior to study enrollment Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to study enrollment History of hemoptysis (≥ ½ teaspoon of bright red blood per episode) within 1 month prior to study enrollment Evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic anticoagulation) Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study enrollment or anticipation of need for major surgical procedure during the course of the study Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to study enrollment History of abdominal fistula, gastrointestinal perforation within 6 months prior to study enrollment Serious, non-healing wound, active ulcer, or untreated bone fracture Proteinuria at screening as demonstrated by either urine protein:creatinine (UPC) ratio ≥ 1.0 at screening OR urine dipstick for proteinuria ≥ 2+ (patients discovered to have ≥2+ proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate ≤ 1g of protein in 24 hours to be eligible). Known hypersensitivity to any component of Avastin Pregnant (positive pregnancy test) or lactation. Use of effective means of contraception (men and women) in subjects of child-bearing potential
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Annick Desjardins, MD, FRCPC
Organizational Affiliation
Duke University
Official's Role
Principal Investigator
Facility Information:
Facility Name
The Preston Robert Tisch Brain Tumor Center at Duke
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Links:
URL
https://tischbraintumorcenter.duke.edu/
Description
The Preston Robert Tisch Brain Tumor Center

Learn more about this trial

Avastin/Radiation (XRT)/Temozolomide (Temodar) Followed by Avastin/Temodar/Topotecan for Glioblastoma

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