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Avastin in Combination With Radiation and Temozolomide Followed by Avastin, Temozolomide, and Topotecan for Glioblastoma Multiformes and Gliosarcomas


Phase 2
18 Years
N/A
Open (Enrolling)
Both
Malignant Glioma, Glioblastoma Multiforme, Gliosarcoma

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Trial Information

Avastin in Combination With Radiation and Temozolomide Followed by Avastin, Temozolomide, and Topotecan for Glioblastoma Multiformes and Gliosarcomas


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.


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

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

6-month Progression-free Survival

Outcome 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.

Outcome Time Frame:

6 months

Safety Issue:

No

Principal Investigator

Annick Desjardins, MD, FRCPC

Investigator Role:

Principal Investigator

Investigator Affiliation:

Duke University

Authority:

United States: Institutional Review Board

Study ID:

Pro00019960

NCT ID:

NCT01004874

Start Date:

December 2009

Completion Date:

December 2013

Related Keywords:

  • Malignant Glioma
  • Glioblastoma Multiforme
  • Gliosarcoma
  • malignant glioma
  • glioblastoma multiforme
  • gliosarcoma
  • Avastin
  • bevacizumab
  • Topotecan
  • Hycamtin
  • Temozolomide
  • Temodar
  • Pro00019960
  • Vredenburgh
  • Duke
  • Glioblastoma
  • Glioma
  • Gliosarcoma

Name

Location

The Preston Robert Tisch Brain Tumor Center at DukeDurham, North Carolina  27710