A Randomized Phase II Trial of Bevacizumab With Irinotecan or Bevacizumab With Temozolomide in Recurrent Glioblastoma
Overview
- Phase
- Phase 2
- Intervention
- Bevacizumab
- Conditions
- Adult Glioblastoma
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 123
- Locations
- 93
- Primary Endpoint
- Number of Participants With Predicted Overall Survival (OS) at 12 Months
- Status
- Completed
- Last Updated
- 7 years ago
Overview
Brief Summary
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.
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.
Investigators
Eligibility 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%
Exclusion Criteria
- Not provided
Arms & Interventions
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.
Intervention: Bevacizumab
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.
Intervention: Temozolomide
Arm II (bevacizumab & irinotecan hydrochloride)
Patients receive bevacizumab IV as in Arm I followed by irinotecan hydrochloride IV over 90 minutes on days 1 and 15.
Intervention: Bevacizumab
Arm II (bevacizumab & irinotecan hydrochloride)
Patients receive bevacizumab IV as in Arm I followed by irinotecan hydrochloride IV over 90 minutes on days 1 and 15.
Intervention: Irinotecan Hydrochloride
Outcomes
Primary Outcomes
Number of Participants With Predicted Overall Survival (OS) at 12 Months
Time Frame: 2 and 8 weeks posttreatment, and every 2 months until 96wks
Magnetic Resonance Imaging with Spectroscopy (MRS or MRSI) metabolic tumor ratios will be used to predict 12-month overall survival (OS). Ratios of NAA/Cho, Cho/Cr, NAA/Cr measured at 2 weeks and 8 weeks and every 2 months until 96wks were used to predict survival, and time to death, evaluated at 96wks, is the determinate of OS at 12 months. Subjects will not be analyzed by arm.
Count/Percentage of Patients Progression-free at 6 Months for Bevacizumab and Irinotecan Hydrochloride Arm
Time Frame: From randomization to six months.
Progression defined as ≥ 25% increase in the size of enhancing tumor or any new tumor; or neurologically worse, and steroids stable or increased. Percentage is calculated by taking the number of patients who have survived 6 months without progression of study disease after study registration in the numerator. The denominator consists of all patients except those who were found retrospectively to be ineligible or who were lost to follow-up after less than 6 months.
Count/Percentage of Patients Discontinuing Treatment 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).
This endpoint determines tolerability of this treatment arm. If tolerable, then the secondary endpoint of treatment efficacy for this arm occurs. Percentage is calculated by taking the number of patients who did not stop bevacizumab and temozolomide treatment due to medical complications in the numerator. The denominator consists of all patients except those who were found retrospectively to be ineligible or who did not begin treatment.
Number of Participants With Predicted Progression-free Survival at 6 Months (PFS-6)
Time Frame: 2 and 8 weeks posttreatment, and every 2 months until 96wks
Magnetic Resonance Imaging with Spectroscopy (MRS or MRSI) metabolic tumor ratios will be used to predict 6-month progression-free survival (PFS-6) over all study participants. Ratios of NAA/Cho, Cho/Cr, NAA/Cr measured at 2 weeks and 8 weeks and every 2 months until 96wks were used to predict survival, and time to progression, evaluated at 96wks, is the determinate of PFS at 6months (PFS-6). Subjects will not be analyzed by arm.
Secondary Outcomes
- Accuracy of Local PFS 6-mo Interpretation Using Central Review PFS-6 as the Reference Standard(baseline visit, week 2, after every 2 cycles of treatment, and at termination of treatment)
- Patients' Best Objective Response (Complete Response, Partial Response, Stable Disease, Progression)(From randomization to death or last follow-up. Patients were followed up to 62.9 months.)
- Correlation of Degree of Cerebral Blood Volume (CBV) and Lactate (Lac) to Patient Response(2 weeks following initiation of protocol treatment (T1))
- Predictive Value of CBV and Lac/NAA in Assessing 6-month Progression-free Survival(2 weeks following initiation of protocol treatment (T1))
- Change in Perfusion MRI Markers at Week 2 as Predictors of 12mo Overall Survival (OS)(Baseline and 2 Weeks)
- Change in Perfusion MRI Markers at Week 8 as Predictors of 12mo Overall Survival (OS)(Baseline and 8 weeks)
- Count/Percentage of Patients Progression-free at 6 Months for Bevacizumab and Temozolomide Arm(From randomization to six months.)
- Agreement Between Local Interpretation and Central Interpretation of Standard MRI(baseline visit, week 2, after every 2 cycles of treatment, and at termination of treatment)
- Correlation of Degree of Cerebral Blood Volume (CBV) and Lactate (Lac) to N-acetylaspartate (NAA) (Lac/NAA) Ratio(2 weeks following initiation of protocol treatment (T1) and at 8 weeks following chemotherapy with bevacizumab (T2))
- Change in Perfusion MRI Markers at Week 16 as Predictors of 12mo Overall Survival (OS)(Baseline and 16 Weeks)