Phase II Avastin + Bortezomib for Patients With Recurrent Malignant Glioma

Phase 2

Completed

Conditions: Glioblastoma
Gliosarcoma

Interventions: Drug: Avastin
Drug: Bortezomib

Registration Number: NCT00611325

Lead Sponsor: Duke University

Brief Summary: Primary Objective To estimate 6-month progression free survival probability of patients with recurrent glioblastoma multiforme treated with bortezomib plus Avastin. This efficacy assessment will be made separately among patients on enzyme-inducing anti-epileptic drugs and non enzyme-inducing anti-epileptic drugs.

Secondary Objectives To evaluate safety \& tolerability of bortezomib plus Avastin among patients with recurrent malignant glioma.

To evaluate radiographic response, progression free survival \& overall survival of patients with recurrent malignant glioma treated with bortezomib plus Avastin

Detailed Description: This is an open-label, 2-arm Phase II study assessing safety \& efficacy of bortezomib in combination with Avastin for patients with recurrent glioblastoma multiforme (gbm). 56 total patients with recurrent WHO grade IV malignant gliomas have been enrolled on study. Avastin was administered intravenously at a dose of 15 mg/kg every 3 weeks. Bortezomib was administered on days 1, 4, 8, 11, 22, 25, 29, \& 32 of a 42-day cycle. The dose of bortezomib was 1.7 mg/m2 for non-EIAED patients \& 2.5 mg/m2 for EIAED patients. Treatment continued until either evidence of progressive disease, unacceptable toxicity, non-compliance with study follow-up / withdrawal of consent. Brain MRIs were obtained after every cycle.

Bortezomib administration is associated with mild toxicity in most patients, such as fatigue, diarrhea \& nausea, constipation \& peripheral neuropathy. Less common, bortezomib administration leads to more significant hematologic toxicities \& peripheral neuropathies. Most significant toxicities associated with Avastin in recently completed phase II clinical trial at Duke were thrombotic complications \& grade 2 proteinuria. "Unacceptable" toxicities rates of 15 percent or less were considered desirable, while rates of 40 percent or greater were considered undesirable. The statistical hypothesis that needed testing differentiated between 15% \& 40% rate of unacceptable toxicity.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 56

Inclusion Criteria

Patients have histologically confirmed diagnosis of recurrent/progressive WHO grade IV malignant glioma (MG)

Age >18 yrs
No prior treatment with bortezomib, & no Avastin in last 3 months, not allowed to have progressed to Avastin regimen. No history of > or equal to grade 2 CNS hemorrhage or grade 3 or higher toxicities while on Avastin
At least 6 weeks from surgical resection, 4 weeks from end of radiotherapy & enrollment in this study
Karnofsky Performance Status (KPS) > or equal to 70%
Hemoglobin (Hgb) > or = to 9 g/deciliter (dL), absolute neutrophil count (ANC) > or = to 1,500 cells/microliter, platelets > or = to 125,000 cells/microliter;
Serum creatinine <1.5 mg/dL, serum glutamic oxalocetic transaminase (SGOT) & bilirubin <1.5 x upper limit of normal
Signed informed consent approved by IRB;
If sexually active, patients must agree to take contraceptive measures for duration of treatments
May have had up to 3 biological therapies (such as tyrosine kinase inhibitors, topoisomerase I or II inhibitors, or rapamycin)

Exclusion Criteria

Gr 2 or greater peripheral neuropathy at time of study enrollment
No prior taxanes, as it predisposes to sensory neuropathy
Co-medication that may interfere with study results, e.g. immuno-suppressive agents other than corticosteroids
Greater than 3 prior recurrences
Evidence of CNS hemorrhage on baseline MRI on CT scan (except for grade 1 hemorrhage that has been stable for at least 3 months)
History of thrombotic or hemorrhagic stroke or myocardial infarction within 6 months
Requires therapeutic anti-coagulation
At least 4 weeks from Day 0 of prior monthly chemotherapy (at least 6 weeks if a nitrosourea). At least 1 week from last dose of daily chemotherapy (such as metronomic temozolomide, cytoxan) or targeted therapies administered daily (such as gleevec, tarceva)
Pregnancy or breast feeding
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring IV antibiotics & psychiatric illness/social situations that would limit compliance with study requirements, or disorders associated with significant immunocompromised state
Patients with another primary malignancy that has required treatment within past year.

Avastin-Specific Concerns:

Any prior history of hypertensive crisis or hypertensive encephalopathy
Systolic blood pressure (BP) > 150 mmHg or diastolic BP > 100 mmHg
Unstable angina
New York Heart Association Gr II or > congestive heart failure
History of myocardial infarction within 6 months
History of stroke within 6 months
Clinically significant peripheral vascular disease
Evidence of bleeding diathesis, coagulopathy as documented by an elevated prothrombin time (PT), partial thromboplastin time (PTT)/bleeding time
Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 0, anticipation of need for major surgical procedure during course of study
Minor surgical procedures, fine needle aspirations or core biopsies within 7 days prior to Day 0
Urine protein: creatinine ratio > or = to 1.0 at screening
History of abdominal fistula, GI perforation, or intra-abdominal abscess within 6 months prior to Day 0
Serious, non-healing wound, ulcer, or bone fracture
Known hypersensitivity to any component of Avastin
Inability to comply with study and/or follow-up procedures

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
EIAED	Avastin	Patients taking enzyme-inducing anti-epileptic drugs (EIAEDs). Avastin was administered intravenously at a dose of 15 mg/kg every 3 weeks. Bortezomib was adminstered intravenously at a dose of 2.5 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32 of a 42-day cycle.
Non-EIAED	Avastin	Patients not taking enzyme-inducing anti-epileptic drugs (EIAEDs). Avastin was administered intravenously at a dose of 15 mg/kg every 3 weeks. Bortezomib was adminstered intravenously at a dose of 1.7 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32 of a 42-day cycle.
EIAED	Bortezomib	Patients taking enzyme-inducing anti-epileptic drugs (EIAEDs). Avastin was administered intravenously at a dose of 15 mg/kg every 3 weeks. Bortezomib was adminstered intravenously at a dose of 2.5 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32 of a 42-day cycle.
Non-EIAED	Bortezomib	Patients not taking enzyme-inducing anti-epileptic drugs (EIAEDs). Avastin was administered intravenously at a dose of 15 mg/kg every 3 weeks. Bortezomib was adminstered intravenously at a dose of 1.7 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32 of a 42-day cycle.

Primary Outcome Measures

Name	Time	Method
6-month Progression-free Survival (PFS)	6 months	Percentage of participants surviving six months from the initiation of treatment without progression of disease. PFS was defined as the time from the initiation of treatment to the date of the first documented progression according to the Macdonald criteria, or to death due to any cause. Per Macdonald, progression is a ≥ 25% increase in the sum of the products of perpendicular diameters of enhancing lesions, any new lesion or clinical deterioration.

Secondary Outcome Measures

Name	Time	Method
Number of Patients With Grade 3 or Greater, Treatment-related, Non-hematologic Toxicities	60 months	Number of patients with grade 3 or greater, treatment-related, non-hematologic toxicities based on Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.
Median Progression Free Survival (PFS)	Time in months from the start of study treatment to the date of first progression or death. Assessed up to 60 months.	Time in months from the start of study treatment to the date of first progression according to Macdonald criteria, or to death due to any cause. Per Macdonald, progression is a ≥ 25% increase in the sum of the products of perpendicular diameters of enhancing lesions, any new lesion, or clinical deterioration. Patients alive who had not progressed as of the last follow-up had PFS censored at the last follow-up date. Median PFS was estimated using a Kaplan-Meier curve.
Median Overall Survival (OS)	Time in months from the start of study treatment to date of death due to any cause. Assessed up to 60 months.	Time in months from the start of study treatment to the date of death. Patients alive as of the last follow-up had OS censored at the last follow-up date. Median OS was estimated using a Kaplan-Meier curve.
Radiographic Response Rate	60 months	The percentage of participants with a complete or partial response at any assessment as determined by the Macdonald criteria. A confirmation of response was not required. Per Macdonald criteria, complete response (CR) was the disappearance of all target lesions and partial response (PR) was a ≥50% decrease in the sum of the longest diameter of target lesions, no new lesions and stable or decreasing steroid dose. Objective response =CR+PR. Tumor assessments were done at baseline and at the end of each 6 week treatment cycle, and overall best response was recorded.