A Study of Temsirolimus and Bevacizumab in Recurrent Glioblastoma Multiforme

Inclusion criteria

• Written informed consent
• Histological verification of primary GBM and failure after radiotherapy and temozolomide (TMZ)
• Previously treated with VEGF-directed therapy with bevacizumab
• Previously received radiotherapy and temozolomide
• More than 4 weeks since any of the following prior treatments: chemotherapy (6 weeks for nitrosoureas or mitomycin C)
• Radiotherapy to nontarget lesions or lesions that are not to be biopsied VEGF-directed therapy (including bevacizumab)
• Investigational agents
• More than 6 months since prior major surgery or open biopsy and recovered (only 6 weeks required if operation is for recurrent GBM)
• No concurrent medications or substances known to affect or with the potential to affect the activity or pharmacokinetics of the following:

• Temsirolimus
• Bevacizumab
• CYP450 isoenzymes
• ECOG performance status 0-1
• WBC ≥ 3,000 mm³
• Absolute neutrophil count ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Bilirubin and phosphate normal
• AST and ALT ≤ 2.5 times upper limit of normal
• Creatinine normal OR creatinine clearance ≥ 60 mL/min
• Urine protein: creatinine ratio < 1.0 OR 24-hour urine protein < 1,000 mg
• Fasting cholesterol < 350 mg/dL (cholesterol medications are allowed)
• Fasting triglycerides < 400 mg/dL
• PT INR ≤ 1.5
• Hematocrit < 41% (for males) or < 38% (for females)
• Fertile females must use an approved contraceptive (p-pills, IUD, depot injection of gestagen, subdermal implantation, hormonal vaginal ring or transdermal depot plaster), throughout the study and 3 months after discontinuation of study drugs. Fertile men must use dobbelt barrier method (preservative with sperm inhibiting creme) or female partner uses the above mentioned contraceptive.
• Fertile males must use preservatives.

Exclusion criteria

• Clinically significant cardiovascular disease, including the following:
• Cerebrovascular accident within the past 6 months
• Transient ischemic attack within the past 6 months
• Myocardial ischemia within the past 6 months
• Myocardial infarction within the past 6 months
• Other thromboembolic event within the past 6 months
• Unstable angina within the past 6 months
• Uncontrolled hypertension (i.e., hypertension despite maximal therapy)
• New York Heart Association class II-IV heart disease
• Congestive heart failure
• Serious cardiac arrhythmia requiring medication
• Clinically significant peripheral vascular disease
• Uncontrolled intercurrent illness
• Ongoing or active infection
• One of the following within the past 6 months
• Abdominal fistula
• Gastrointestinal perforation
• Intra-abdominal abscess
• Serious or nonhealing wound, ulcer, or bone fracture
• Psychiatric illness or social situations that would preclude study compliance
• Uncontrolled diabetes
• Hemoglobin A1c > 7%
• Concurrent non-study related surgical procedures
• Concurrent treatment with CYP3A4 inducers or inhibitors
• Other concurrent anticancer agents or therapies
• Significant traumatic injury within the past 28 days
• History of allergic reactions to compounds of similar chemical or biological composition to temsirolimus or bevacizumab
• Hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies (e.g., infliximab)
• Pregnancy or nursing
• Patients previously intolerant to bevacizumab
• Anticoagulant therapy