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Bevacizumab Beyond Progression (BBP)

Study Purpose

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.

Recruitment Criteria

Accepts Healthy Volunteers

Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms

No
Study Type

An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.


An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.


Searching Both is inclusive of interventional and observational studies.

Interventional
Eligible Ages 18 Years and Over
Gender All
More Inclusion & Exclusion 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;

Trial Details

Trial ID:

This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.

NCT01740258
Phase

Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.

Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.

Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.

Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.

Phase 2
Lead Sponsor

The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.

Duke University
Principal Investigator

The person who is responsible for the scientific and technical direction of the entire clinical study.

Annick Desjardins, MD, FRCPC
Principal Investigator Affiliation Duke Health
Agency Class

Category of organization(s) involved as sponsor (and collaborator) supporting the trial.

Other, Industry
Overall Status Completed
Countries United States
Conditions

The disease, disorder, syndrome, illness, or injury that is being studied.

Malignant Glioma, Grade 4 Malignant Glioma, Glioblastoma, Gliosarcoma
Study Website: View Trial Website
Additional Details

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.

Arms & Interventions

Arms

Experimental: Bevaczimab, Radiation Therapy, Temozolomide

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.

Interventions

Radiation: - Radiation Therapy

Drug: - Temozolomide

Drug: - Bevacizumab

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.

Duke Cancer Center, Durham, North Carolina

Status

Address

Duke Cancer Center

Durham, North Carolina, 27710