Bevacizumab and Irinotecan or Temozolomide in Treating Patients With Recurrent or Refractory Glioblastoma Multiforme or Gliosarcoma

This study has been completed.
Sponsor:
Collaborator:
American College of Radiology Imaging Network
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00433381
First received: February 8, 2007
Last updated: May 7, 2014
Last verified: November 2012
  Purpose

This randomized phase II trial is studying the side effects and how well giving bevacizumab together with irinotecan or temozolomide works in treating patients with recurrent or refractory glioblastoma multiforme or gliosarcoma. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Drugs used in chemotherapy, such as irinotecan and temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving bevacizumab together with irinotecan or temozolomide may kill more tumor cells.


Condition Intervention Phase
Adult Glioblastoma
Adult Gliosarcoma
Recurrent Adult Brain Tumor
Drug: irinotecan hydrochloride
Biological: bevacizumab
Drug: temozolomide
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Randomized Phase II Trial of Bevacizumab With Irinotecan or Bevacizumab With Temozolomide in Recurrent Glioblastoma

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Six-month Progression-free Survival (PFS) for Bevacizumab and Irinotecan Hydrochloride Arm [ Time Frame: From randomization to six months. ] [ Designated as safety issue: No ]
    Progression-free survival is defined as time from randomization to date of progression or date of death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive without progression are considered to be censored at the date of last contact.

  • Rate of Treatment Discontinuation Due to Treatment-related Medical Complications(Bevacizumab and Temozolomide Arm) [ Time Frame: From randomization to end of treatment (treatment can continue up to 24 months for patients with stable or responding tumor). ] [ Designated as safety issue: Yes ]
    If 6 or fewer of 29 patients stop treatment due to medical conditions, then null hypothesis of rate = 0.35 will be rejected, type I and type II error of 0.10. Alternative hypothesis rate of 0.15.


Secondary Outcome Measures:
  • Six-month Progression-free Survival (Bevacizumab and Temozolomide Arm) [ Time Frame: From randomization to six months. ] [ Designated as safety issue: No ]
  • Best Objective Response Rate (Complete Response, Partial Response, Stable Disease, Progression) in Both Arms [ Time Frame: From randomization to progression, death, or last follow-up. ] [ Designated as safety issue: No ]
    Only patients who have measurable disease present at baseline will be considered evaluable for response except those who are removed from the study before the end of cycle 1 for reasons other than clinical progression (such as toxicity). Tumor size will be measured in millimeters and is the largest crosssectional area using perpendicular measurements of contrast enhancing abnormality. Complete response (CR): Complete disappearance of all enhancing tumor on consecutive MRI scans at least 1 month apart, off corticosteroids, and neurologically stable or improved. Partial response (PR): ≥ 50% decrease in size of enhancing tumor on consecutive MRI scans at least 1 month apart, corticosteroids stable or reduced, and neurologically stable or improved. Stable disease (SD): Does not qualify for CR, PR, or PD. Progression: ≥ 25% increase in the size of enhancing tumor or any new tumor; or neurologically worse, and steroids stable or increased.

  • Agreement Between Local Interpretation and Central Interpretation of the Standard MRI on the 6-month Progression-free Survival [ Time Frame: From randomization to six months. ] [ Designated as safety issue: No ]
    Assessed using a McNemar's test. The sensitivity and specificity of the local interpretation of the 6-month progression-free survival will be estimated using the central review as the reference standard. In particular, for patients progressed at 6 months according to central review, the sensitivity of the local interpretation will be estimated and the exact confidence interval will be calculated. The specificity and the associated exact confidence interval of the local interpretation will be calculated in a similar way.

  • Accuracy of Local Interpretation on the 6-month Progression-free Survival Using Central Review as the Reference Standard [ Time Frame: From randomization to six months. ] [ Designated as safety issue: No ]
  • Correlation of Degree of Cerebral Blood Volume (CBV) and Lactate (Lac) to N-acetylaspartate (NAA) (Lac/NAA) Ratio [ Time Frame: From registration to two weeks following initiation of bevacizumab. ] [ Designated as safety issue: No ]
  • Correlation of Degree of Cerebral Blood Volume (CBV) and Lactate (Lac) to Patient Response [ Time Frame: From randomization to two weeks following initiation of bevacizumab. ] [ Designated as safety issue: No ]
  • Predictive Value of CBV and Lac/NAA in Assessing 6-month Progression-free Survival [ Time Frame: From randomization to six months. ] [ Designated as safety issue: No ]

Enrollment: 123
Study Start Date: March 2007
Study Completion Date: February 2011
Primary Completion Date: January 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I (bevacizumab and temozolomide)
Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and oral temozolomide once daily on days 1-21.
Biological: bevacizumab
Given IV
Other Names:
  • anti-VEGF humanized monoclonal antibody
  • anti-VEGF monoclonal antibody
  • Avastin
  • rhuMAb VEGF
Drug: temozolomide
Given orally
Other Names:
  • SCH 52365
  • Temodal
  • Temodar
  • TMZ
Experimental: Arm II (bevacizumab and irinotecan hydrochloride)
Patients receive bevacizumab IV as in Arm I followed by irinotecan hydrochloride IV over 90 minutes on days 1 and 15.
Drug: irinotecan hydrochloride
Given IV
Other Names:
  • Campto
  • Camptosar
  • CPT-11
  • irinotecan
  • U-101440E
Biological: bevacizumab
Given IV
Other Names:
  • anti-VEGF humanized monoclonal antibody
  • anti-VEGF monoclonal antibody
  • Avastin
  • rhuMAb VEGF

Detailed Description:

PRIMARY OBJECTIVES:

I. Determine the efficacy of bevacizumab and irinotecan hydrochloride, in terms of 6-month progression-free survival rate, in patients with recurrent or refractory intracranial glioblastoma multiforme or gliosarcoma.

II. Determine the adverse event profile and tolerability of bevacizumab and temozolomide in these patients.

SECONDARY OBJECTIVES:

I. Determine the efficacy of bevacizumab and temozolomide, in terms of 6-month progression-free survival rate, in patients previously treated with temozolomide.

II. Determine the efficacy of bevacizumab and irinotecan hydrochloride, in terms of objective response, in patients with measurable disease.

III. Determine the efficacy of bevacizumab and temozolomide, in terms of objective response, in patients with measurable disease who were previously treated with temozolomide.

IV. Determine the toxicity profile and tolerability of bevacizumab and irinotecan hydrochloride in these patients.

TERTIARY OBJECTIVES:

I. Assess the potential role of perfusion MRI and magnetic resonance spectroscopy imaging as an early indicator of response to therapy after 2 weeks of treatment with bevacizumab.

II. Assess the potential role of perfusion MRI and magnetic resonance spectroscopy imaging as a prognostic indicator based on images taken at baseline, at 2 weeks, and after 2 courses of study treatment.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to age (< 50 vs >= 50 years of age) and Karnofsky performance status (70-80% vs 90-100%). Patients are randomized to 1 of 2 treatment arms with a 2:1 ratio (arm I:arm II).

ARM I: Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and oral temozolomide once daily on days 1-21.

ARM II: Patients receive bevacizumab IV as in Arm I followed by irinotecan hydrochloride IV over 90 minutes on days 1 and 15.

In both arms, treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. All patients undergo MRI at baseline and at every 2 courses (no 2-week MRI) per standard of care until progression or discontinuation of treatment to assess areas of breakdown of the blood-brain barrier. Patients undergo an additional MRI after study therapy. Consenting patients also undergo diffusion and perfusion MRI and magnetic resonance spectroscopic imaging for correlative studies.

After completion of study therapy, patients are followed up for at least 1 month.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically confirmed intracranial glioblastoma multiforme (GBM) or gliosarcoma

    • Original histology of low-grade glioma with subsequent histological diagnosis of GBM or gliosarcoma allowed
  • Recurrent or refractory disease, meeting all of the following criteria:

    • Must have received prior temozolomide
    • Pathologic or imaging confirmation of tumor progression or regrowth required

      • Confirmation of true progressive disease (rather than radiation necrosis) by positron emission tomography, thallium scanning, MRI spectroscopy, or surgical documentation required for patients who received prior interstitial brachytherapy, Gliadel wafer, or stereotactic radiosurgery
  • Unequivocal radiographic evidence of tumor progression by MRI within the past 14 days (while on a stable dose of steroids for ≥ 5 days)
  • No acute intratumoral hemorrhage on MRI

    • Patients with MRI demonstrating old hemorrhage or subacute blood after a neurosurgical procedure (biopsy or resection) are eligible
  • Karnofsky performance status 70-100%
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception during and for at least 6 months after completion of bevacizumab therapy
  • Systolic blood pressure ≤ 160 mm Hg or diastolic blood pressure ≤ 90 mm Hg (antihypertensive medication allowed)
  • Able to undergo brain MRI scans with intravenous gadolinium
  • Absolute neutrophil count ≥ 1,500 cells/mm³
  • Platelet count ≥ 100,000 cells/mm³
  • Hemoglobin ≥ 10 g/dL (transfusion or other intervention allowed)
  • WBC ≥ 3,000 cells/mm³
  • AST < 2 times upper limit of normal
  • Bilirubin ≤ 1.6 mg/dL
  • Creatinine < 1.5 mg/dL
  • Urine protein:creatinine ratio ≤ 0.5 by urinalysis OR total urinary protein < 1,000 mg by 24-hour urine collection
  • INR < 1.4 (for patients not on warfarin)
  • No patients with severely impaired renal function (i.e., estimated glomerular filtration rate < 30 mL/min or on dialysis)
  • No other prior invasive malignancy, except nonmelanomatous skin cancer or carcinoma in situ of the cervix, unless the patient has been disease free and off therapy for that disease for ≥ 3 years
  • No severe, active comorbidity, defined as any of the following:

    • Transmural myocardial infarction or unstable angina within the past 6 months
    • Evidence of recent myocardial infarction or ischemia manifested as ST elevation of ≥ 2 mm by EKG performed within the past 14 days
    • New York Heart Association class II-IV congestive heart failure requiring hospitalization within the past 12 months
    • History of stroke or transient ischemic attack within the past 6 months
    • Cerebrovascular accident within the past 6 months
    • Serious and inadequately controlled cardiac arrhythmia
    • Significant vascular disease (e.g., aortic aneurysm or history of aortic dissection)
    • Clinically significant peripheral vascular disease
    • Evidence of bleeding diathesis or coagulopathy
    • Serious or nonhealing wound, ulcer, or bone fracture
    • Abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 28 days
    • Acute bacterial or fungal infection requiring intravenous antibiotics at the time of study entry
    • Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within the past 14 days
    • Acquired immune deficiency syndrome (AIDS)
  • No significant traumatic injury within the past 28 days
  • No known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
  • No condition that impairs the ability to swallow pills (e.g., gastrointestinal tract disease resulting in an inability to take oral medication; requirement for IV alimentation; prior surgical procedures affecting absorption; or active peptic ulcer disease)
  • No disease that would obscure toxicity or dangerously alter drug metabolism
  • No concurrent major surgical procedures
  • Recovered from prior therapy
  • Recent resection of recurrent or progressive tumor allowed provided the following criteria are met:

    • Failed prior radiotherapy that was completed ≥ 42 days ago
    • Residual disease after resection of recurrent glioblastoma is not mandated
  • More than 28 days since prior surgery or open biopsy
  • More than 7 days since prior core or needle biopsy
  • At least 28 days since prior investigational agents
  • At least 14 days since prior vincristine
  • At least 42 days since prior nitrosoureas
  • At least 21 days since prior procarbazine
  • At least 28 days since other prior cytotoxic therapy
  • At least 7 days since prior noncytotoxic agents (e.g., interferon, tamoxifen, thalidomide, or isotretinoin [except radiosensitizers])
  • At least 14 days since prior enzyme-inducing antiepileptic drugs (EIAEDs)

    • Concurrent non-hepatic EIAEDs allowed
  • No other concurrent CYP3A4 inducers, such as rifampin or Hypericum perforatum (St. John's wort)
  • Concurrent full-dose anticoagulants (e.g., warfarin or low molecular weight heparin) allowed provided all of the following criteria are met:

    • No active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices)
    • In-range INR (usually between 2 and 3) on a stable dose of oral anticoagulants or on a stable dose of low molecular weight heparin
  • No concurrent highly active antiretroviral therapy
  • No concurrent prophylactic use of growth factors
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00433381

  Show 51 Study Locations
Sponsors and Collaborators
American College of Radiology Imaging Network
Investigators
Principal Investigator: Mark Gilbert Radiation Therapy Oncology Group
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00433381     History of Changes
Other Study ID Numbers: NCI-2009-00743, NCI-2009-00743, RTOG-0625, ACRIN-6677, CDR0000528259, RTOG 0625, RTOG-0625, U10CA021661
Study First Received: February 8, 2007
Results First Received: March 14, 2013
Last Updated: May 7, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Glioblastoma
Gliosarcoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Bevacizumab
Temozolomide
Irinotecan
Dacarbazine
Camptothecin
Antibodies
Antibodies, Monoclonal
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Pharmacologic Actions
Growth Inhibitors
Antineoplastic Agents
Therapeutic Uses
Immunologic Factors
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on September 22, 2014