search
Back to results

Bevacizumab Beyond Progression (BBP) (BBP)

Primary Purpose

Malignant Glioma, Grade 4 Malignant Glioma, Glioblastoma

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Radiation Therapy
Temozolomide
Bevacizumab
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, Grade 4 malignant glioma, glioblastoma, gliosarcoma, adult brain tumor

Eligibility Criteria

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

Inclusion Criteria:

  • Patients with histologically confirmed WHO Grade IV primary malignant glioma (glioblastoma or gliosarcoma);
  • Patients ≥ 18 years of age;
  • An interval of at least 2 weeks, but not ≥ 8 weeks between prior surgical procedure and initiation of treatment;
  • Karnofsky Performance Status (KPS) ≥ 60%
  • Laboratory Values:

    • Platelet Count ≥ 125,000 cells/µL
    • Absolute neutrophil count (ANC) ≥ 1,500 cells/µL
    • Adequate renal function indicated by all of the following:

      • Serum creatinine ≤ 1.25 x upper limit of normal (ULN) or calculated creatinine clearance ≥ 50 ml/min
      • Urine dipstick for proteinuria < 2+ unless a 24-hour urine protein < 1 g of protein is demonstrated
    • internationalized normalized ratio (INR) ≤ 1.5 and activated partial thromboplastin time (aPTT) ≤ 1.5 x upper limit of normal (ULN) within 7 days prior to first study treatment for patients not receiving anti-coagulation. The use of full-dose oral or parenteral anticoagulants is permitted as long as the INR or aPTT is within therapeutic limits (according to the medical standard of the enrolling institution) and the patient has been on a stable dose of anticoagulants for at least two weeks prior to the first study treatment.
  • Patients will sign an Institutional Review Board-approved informed consent form.
  • Female patients must not be pregnant or breast-feeding. Female patients of childbearing potential (defined as < 2 years after last menstruation or not surgically sterile) must use a highly effective contraceptive method (allowed methods of birth control, [i.e. with a failure rate of < 1% per year] are implants, injectables, combined oral contraceptives, intra-uterine device [Intrauterine Device (IUD); only hormonal], sexual abstinence or vasectomized partner) during the trial and for a period of > 6 months following the last administration of trial drug(s). Female patients with an intact uterus (unless amenorrhea for the last 24 months) must have a negative serum pregnancy test within 7 days prior to first study treatment.
  • Fertile male patients must agree to use a highly effective contraceptive method (allowed methods of birth control [i.e. with a failure rate of < 1% per year] include a female partner using implants, injectables, combined oral contraceptives, Intrauterine Device (IUDs) [only hormonal], sexual abstinence or prior vasectomy) during the trial and for a period of > 6 months following the last administration of trial drugs.

Exclusion Criteria:

  • Any prior treatment for any grade glioma, including, but not limited to gliadel wafers, immunotherapy (including vaccine therapy), radiation therapy or chemotherapy, irrespective of grade of the tumor (NOTE: 5-aminolevulinic acid (ALA)-mediated photodynamic therapy administered prior to surgery to aid in optimal surgical resection is not considered a chemotherapy agent.);
  • Co-medication that may interfere with study results; e.g. immuno-suppressive agents other than corticosteroids;
  • Active infection requiring intravenous antibiotics;
  • Prior or current treatment with bevacizumab or other anti-angiogenic treatment (i.e. anti-vascular endothelial growth factor (VEGF) or vascular endothelial growth factor receptor (VEGFR) therapies or tyrosine kinase inhibitors) for any condition;
  • Treatment with any other investigational agent within 28 days or 2 investigational agent half-lives (whichever is longer) prior to first study treatment;
  • Prior, unrelated malignancy requiring current active treatment with the exception of cervical carcinoma in situ and adequately treated basal cell or squamous cell carcinoma of the skin;
  • Evidence of > Grade 1 central nervous system (CNS) hemorrhage on post-operative MRI scan, unless repeat MRI or CT performed prior to initiating bevacizumab shows stable grade 1 or resolving (< grade 1) CNS hemorrhage.

Bevacizumab-Specific Exclusion Criteria:

  • Inadequately controlled hypertension (defined as systolic blood pressure > 150 mmHg and/or diastolic blood pressure > 100 mmHg) within 28 days of first study treatment;
  • Prior history of hypertensive crisis, hypertensive encephalopathy, reverse posterior leukoencephalopathy syndrome (RPLS);
  • Prior history of gastrointestinal perforation or abscess;
  • Clinically significant (i.e. active) cardiovascular disease, for example cerebrovascular accidents ≤ 6 months prior to study enrollment, myocardial infarction ≤ 6 months prior to study enrollment, unstable angina, New York Heart Association (NYHA) Grade II or greater congestive heart failure (CHF), or serious cardiac arrhythmia uncontrolled by medication or potentially interfering with protocol treatment;
  • History or evidence upon physical/neurological examination of central nervous system disease (e.g. seizures) unrelated to cancer unless adequately controlled by medication or potentially interfering with protocol treatment;
  • Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months prior to start of study treatment. Any previous venous thromboembolism > NCI common toxicity criteria adverse event (CTCAE) Grade 3;
  • History of pulmonary hemorrhage/hemoptysis ≥ grade 2 (defined as ≥ 2.5 mL bright red blood per episode) within 1 month of first study treatment;
  • History or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding (i.e. in the absence of therapeutic anticoagulation);
  • Current or recent (within 10 days of study enrollment) use of aspirin (>325 mg/day), clopidogrel (>75 mg/day) or equivalent. Prophylactic use of anticoagulants is allowed;
  • Surgical procedure (including open biopsy, surgical resection, wound revision, or any other major surgery involving entry into a body cavity) or significant traumatic injury within 28 days prior to first study treatment, or anticipation of need for major surgical procedure during the course of the study;
  • Minor surgical procedure, e.g. stereotactic biopsy, within 7 days of first study treatment; placement of a vascular access device, within 2 days of first study treatment;
  • History of intracranial abscess within 6 months prior to first study treatment;
  • History of active gastrointestinal bleeding within 6 months prior to first study treatment;
  • Serious, non-healing wound, active ulcer, or untreated bone fracture;
  • Known hypersensitivity to any component of bevacizumab or any of the study drugs;

Sites / Locations

  • Duke Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Bevaczimab, Radiation Therapy, Temozolomide

Arm Description

In Part A, newly-diagnosed patients with Grade 4 malignant gliomas will receive standard radiation therapy, daily Temodar 75mg/M for 6-8 weeks. Bevacizumab will be given concurrently with radiation therapy and Temodar, 10 mg/kg every two weeks. If they are stable at the end of Part A, they will continue to Part B. In Part B patients will receive up to 12 cycles of bevacizumab and Temodar. Bevacizumab will be given on Days 1 and 15 of a 28-day cycle. Temodar will be 200 mg/meter squared daily for 5 days (days 1-5) of each cycle. If they have not progressed, patients will start Part C. In Part C, patients will receive bevacizumab 10mg/kg approximately every 2 weeks or 15 mg/kg approximately every 3 weeks. If patients progress during Part B or C, they will start Part D. In Part D, patients will receive bevacizumab-based therapy containing bevacizumab in combination with a chemotherapy and/or biologic agent, as determined by the Duke treating physician.

Outcomes

Primary Outcome Measures

Overall Survival
To assess the effect on overall survival of continuing bevacizumab treatment after disease progression in patients treated with bevacizumab from the time of first diagnosis of grade IV malignant glioma.

Secondary Outcome Measures

Toxicity: Percentage of Subjects With Unacceptable Toxicities
The occurrence of ≥ grade 2 CNS (central nervous system) hemorrhage or grade 4 or 5 non-hematologic toxicity is defined as being unacceptable. "Unacceptable" toxicity rates of 5% or less are considered desirable, while rates of 20% or greater are considered as undesirable.
Progression-free Survival (PFS)
To assess the effect on progression-free survival of continuing bevacizumab treatment after disease progression in patients treated with bevacizumab from the time of initiation of treatment to the first occurrence of progression, or death

Full Information

First Posted
November 30, 2012
Last Updated
January 6, 2021
Sponsor
Duke University
Collaborators
Genentech, Inc.
search

1. Study Identification

Unique Protocol Identification Number
NCT01740258
Brief Title
Bevacizumab Beyond Progression (BBP)
Acronym
BBP
Official Title
Phase II Trial of Bevacizumab, Radiation Therapy and Temodar Followed by Bevacizumab and Temodar With Continuation of Bevacizumab Beyond Progression (BBP-Bevacizumab Beyond Progression)
Study Type
Interventional

2. Study Status

Record Verification Date
January 2021
Overall Recruitment Status
Completed
Study Start Date
January 2013 (Actual)
Primary Completion Date
November 14, 2019 (Actual)
Study Completion Date
November 14, 2019 (Actual)

3. Sponsor/Collaborators

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

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Studies which have separately studied bevacizumab for recurrent gliomas and bevacizumab for newly-diagnosed glioma have shown good results and the regimens have been well-tolerated by patients. This study seeks to investigate the use of bevacizumab with the standard therapy (radiation therapy and temozolomide) in newly diagnosed patients, followed by bevacizumab and temozolomide with the continuation of bevacizumab following progression. Two critical questions remain- the role of bevacizumab maintenance and bevacizumab at the time of progression in a patient previously treated with bevacizumab at the time of initial diagnosis.
Detailed Description
Given the possible synergism with irinotecan and bevacizumab for colorectal carcinomas, the combination has been studied in gliomas. In a study of 21 patients, the combination of irinotecan and bevacizumab produced a 43% response rate, with acceptable toxicity. The response rate is significantly higher than irinotecan alone and any other therapy for recurrent glioma. There were two serious adverse events, one intracranial hemorrhage and one bowel perforation. At the Duke Brain Tumor Center, the investigators have treated over 1000 glioblastoma patients with a bevacizumab-containing regimen, and there is marked clinical benefit and acceptable toxicity. Our initial study looking at the combination of bevacizumab and irinotecan for patients with recurrent glioblastoma published in 2007 found impressive response rates and survival and corroborated the earlier experience of Starks-Vance. The investigators completed a study for newly diagnosed glioblastoma that utilized bevacizumab, radiation therapy and temozolomide followed by 6 months of bevacizumab, irinotecan and temozolomide. In addition, the group at University of California at Los Angeles published a study with bevacizumab, radiation therapy and temozolomide followed by 12 months of bevacizumab and temozolomide for newly diagnosed glioblastoma. These two phase II studies reported acceptable toxicity and a suggestion of improved survival compared to historical controls, and led to two large phase III randomized, placebo controlled studies of the addition of bevacizumab for newly diagnosed glioblastoma patients. The current proposal builds on the encouraging results of the addition of bevacizumab to the standard therapy for newly diagnosed glioblastoma patients. Two critical questions remain- the role of bevacizumab maintenance and bevacizumab at the time of progression in a patient previously treated with bevacizumab at the time of initial diagnosis. In addition, a retrospective analysis of data collected at our center from patients with recurrent disease suggests that continuation of bevacizumab at the time of progression may improve overall survival in comparison with cessation of bevacizumab.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Malignant Glioma, Grade 4 Malignant Glioma, Glioblastoma, Gliosarcoma
Keywords
malignant glioma, Grade 4 malignant glioma, glioblastoma, gliosarcoma, adult brain tumor

7. Study Design

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

8. Arms, Groups, and Interventions

Arm Title
Bevaczimab, Radiation Therapy, Temozolomide
Arm Type
Experimental
Arm Description
In Part A, newly-diagnosed patients with Grade 4 malignant gliomas will receive standard radiation therapy, daily Temodar 75mg/M for 6-8 weeks. Bevacizumab will be given concurrently with radiation therapy and Temodar, 10 mg/kg every two weeks. If they are stable at the end of Part A, they will continue to Part B. In Part B patients will receive up to 12 cycles of bevacizumab and Temodar. Bevacizumab will be given on Days 1 and 15 of a 28-day cycle. Temodar will be 200 mg/meter squared daily for 5 days (days 1-5) of each cycle. If they have not progressed, patients will start Part C. In Part C, patients will receive bevacizumab 10mg/kg approximately every 2 weeks or 15 mg/kg approximately every 3 weeks. If patients progress during Part B or C, they will start Part D. In Part D, patients will receive bevacizumab-based therapy containing bevacizumab in combination with a chemotherapy and/or biologic agent, as determined by the Duke treating physician.
Intervention Type
Radiation
Intervention Name(s)
Radiation Therapy
Other Intervention Name(s)
XRT
Intervention Type
Drug
Intervention Name(s)
Temozolomide
Other Intervention Name(s)
temo, temodar
Intervention Type
Drug
Intervention Name(s)
Bevacizumab
Other Intervention Name(s)
Avastin
Primary Outcome Measure Information:
Title
Overall Survival
Description
To assess the effect on overall survival of continuing bevacizumab treatment after disease progression in patients treated with bevacizumab from the time of first diagnosis of grade IV malignant glioma.
Time Frame
5 Years
Secondary Outcome Measure Information:
Title
Toxicity: Percentage of Subjects With Unacceptable Toxicities
Description
The occurrence of ≥ grade 2 CNS (central nervous system) hemorrhage or grade 4 or 5 non-hematologic toxicity is defined as being unacceptable. "Unacceptable" toxicity rates of 5% or less are considered desirable, while rates of 20% or greater are considered as undesirable.
Time Frame
5 Years
Title
Progression-free Survival (PFS)
Description
To assess the effect on progression-free survival of continuing bevacizumab treatment after disease progression in patients treated with bevacizumab from the time of initiation of treatment to the first occurrence of progression, or death
Time Frame
5 Years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients with histologically confirmed WHO Grade IV primary malignant glioma (glioblastoma or gliosarcoma); Patients ≥ 18 years of age; An interval of at least 2 weeks, but not ≥ 8 weeks between prior surgical procedure and initiation of treatment; Karnofsky Performance Status (KPS) ≥ 60% Laboratory Values: Platelet Count ≥ 125,000 cells/µL Absolute neutrophil count (ANC) ≥ 1,500 cells/µL Adequate renal function indicated by all of the following: Serum creatinine ≤ 1.25 x upper limit of normal (ULN) or calculated creatinine clearance ≥ 50 ml/min Urine dipstick for proteinuria < 2+ unless a 24-hour urine protein < 1 g of protein is demonstrated internationalized normalized ratio (INR) ≤ 1.5 and activated partial thromboplastin time (aPTT) ≤ 1.5 x upper limit of normal (ULN) within 7 days prior to first study treatment for patients not receiving anti-coagulation. The use of full-dose oral or parenteral anticoagulants is permitted as long as the INR or aPTT is within therapeutic limits (according to the medical standard of the enrolling institution) and the patient has been on a stable dose of anticoagulants for at least two weeks prior to the first study treatment. Patients will sign an Institutional Review Board-approved informed consent form. Female patients must not be pregnant or breast-feeding. Female patients of childbearing potential (defined as < 2 years after last menstruation or not surgically sterile) must use a highly effective contraceptive method (allowed methods of birth control, [i.e. with a failure rate of < 1% per year] are implants, injectables, combined oral contraceptives, intra-uterine device [Intrauterine Device (IUD); only hormonal], sexual abstinence or vasectomized partner) during the trial and for a period of > 6 months following the last administration of trial drug(s). Female patients with an intact uterus (unless amenorrhea for the last 24 months) must have a negative serum pregnancy test within 7 days prior to first study treatment. Fertile male patients must agree to use a highly effective contraceptive method (allowed methods of birth control [i.e. with a failure rate of < 1% per year] include a female partner using implants, injectables, combined oral contraceptives, Intrauterine Device (IUDs) [only hormonal], sexual abstinence or prior vasectomy) during the trial and for a period of > 6 months following the last administration of trial drugs. Exclusion Criteria: Any prior treatment for any grade glioma, including, but not limited to gliadel wafers, immunotherapy (including vaccine therapy), radiation therapy or chemotherapy, irrespective of grade of the tumor (NOTE: 5-aminolevulinic acid (ALA)-mediated photodynamic therapy administered prior to surgery to aid in optimal surgical resection is not considered a chemotherapy agent.); Co-medication that may interfere with study results; e.g. immuno-suppressive agents other than corticosteroids; Active infection requiring intravenous antibiotics; Prior or current treatment with bevacizumab or other anti-angiogenic treatment (i.e. anti-vascular endothelial growth factor (VEGF) or vascular endothelial growth factor receptor (VEGFR) therapies or tyrosine kinase inhibitors) for any condition; Treatment with any other investigational agent within 28 days or 2 investigational agent half-lives (whichever is longer) prior to first study treatment; Prior, unrelated malignancy requiring current active treatment with the exception of cervical carcinoma in situ and adequately treated basal cell or squamous cell carcinoma of the skin; Evidence of > Grade 1 central nervous system (CNS) hemorrhage on post-operative MRI scan, unless repeat MRI or CT performed prior to initiating bevacizumab shows stable grade 1 or resolving (< grade 1) CNS hemorrhage. Bevacizumab-Specific Exclusion Criteria: Inadequately controlled hypertension (defined as systolic blood pressure > 150 mmHg and/or diastolic blood pressure > 100 mmHg) within 28 days of first study treatment; Prior history of hypertensive crisis, hypertensive encephalopathy, reverse posterior leukoencephalopathy syndrome (RPLS); Prior history of gastrointestinal perforation or abscess; Clinically significant (i.e. active) cardiovascular disease, for example cerebrovascular accidents ≤ 6 months prior to study enrollment, myocardial infarction ≤ 6 months prior to study enrollment, unstable angina, New York Heart Association (NYHA) Grade II or greater congestive heart failure (CHF), or serious cardiac arrhythmia uncontrolled by medication or potentially interfering with protocol treatment; History or evidence upon physical/neurological examination of central nervous system disease (e.g. seizures) unrelated to cancer unless adequately controlled by medication or potentially interfering with protocol treatment; Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months prior to start of study treatment. Any previous venous thromboembolism > NCI common toxicity criteria adverse event (CTCAE) Grade 3; History of pulmonary hemorrhage/hemoptysis ≥ grade 2 (defined as ≥ 2.5 mL bright red blood per episode) within 1 month of first study treatment; History or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding (i.e. in the absence of therapeutic anticoagulation); Current or recent (within 10 days of study enrollment) use of aspirin (>325 mg/day), clopidogrel (>75 mg/day) or equivalent. Prophylactic use of anticoagulants is allowed; Surgical procedure (including open biopsy, surgical resection, wound revision, or any other major surgery involving entry into a body cavity) or significant traumatic injury within 28 days prior to first study treatment, or anticipation of need for major surgical procedure during the course of the study; Minor surgical procedure, e.g. stereotactic biopsy, within 7 days of first study treatment; placement of a vascular access device, within 2 days of first study treatment; History of intracranial abscess within 6 months prior to first study treatment; History of active gastrointestinal bleeding within 6 months prior to first study treatment; Serious, non-healing wound, active ulcer, or untreated bone fracture; Known hypersensitivity to any component of bevacizumab or any of the study drugs;
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Annick Desjardins, MD, FRCPC
Organizational Affiliation
Duke Health
Official's Role
Principal Investigator
Facility Information:
Facility Name
Duke Cancer Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States

12. IPD Sharing Statement

Links:
URL
http://www.cancer.duke.edu/btc/
Description
Preston Robert Tisch Brain Tumor Center at Duke
URL
http://www.dukecancerinstitute.org/
Description
Duke Cancer Institute
URL
http://www.dukehealth.org/cancer/locations/duke-cancer-center
Description
Duke Cancer Center - Patient Care

Learn more about this trial

Bevacizumab Beyond Progression (BBP)

We'll reach out to this number within 24 hrs