RTOG 1122 PHASE II DOUBLE-BLINDED PLACEBO-CONTROLLED STUDY OF BEVACIZUMAB WITH OR WITHOUT AMG 386 IN PATIENTS WITH RECURRENT GLIOBLASTOMA OR GLIOSARCOMA
aMG 386 is a novel Fc fusion protein that sequesters ang1 and ang2, thereby preventing their interaction with Tie2. interim analysis from a phase ib study of aMG 386 and bevacizumab 15 mg/kg every 3 weeks in solid tumors suggests that most treatment-emergent aes were mild and consistent with the respective single-agent toxicity profiles. no pharmacokinetic interactions have been identified between aMG 386 and bevacizumab. it was concluded from prior phase i studies that aMG 386 15 mg/kg weekly can be feasibly combined with bevacizumab 15 mg/kg every 3 weeks. Since the typical bevacizumab dosing schedule for patients with recurrent GBM is 10 mg/kg every 2 weeks, we propose a run-in safety
component to confirm the safety and tolerability of aMG 386 15 mg/kg weekly in combination with bevacizumab 10 mg/kg iV once every 2 weeks.
3.1.1 Histologically proven diagnosis of glioblastoma or variants (gliosarcoma, glioblastoma with
oligodendroglial features, giant cell glioblastoma). Patients will be eligible if the original histology was a lower grade glioma and a subsequent histological diagnosis of glioblastoma or variants is made.
3.1.2 The tumor must be supratentorial. Patients with infratentorial disease, spinal cord disease, and/orleptomeningeal disease are excluded.
3.1.3 Patients must have shown unequivocal evidence for tumor progression on the previous treatment regimen (prior to enrollment on this study) by MRI scan of the brain with and without contrast within 14 days prior to registration. The dose of steroids must be stable or decreasing for at least 5 days prior to the scan. Patients with tumor progression who then undergo surgical resection prior to enrollment on study may be eligible as long as pathology confirms progressive or recurrent GBM (or variants). For patients who undergo surgical resection, registration on study may not occur any sooner than 28 days from surgery; an MRI scan of the brain with and without contrast is still required within 14 days prior to registration on study but is not required to demonstrate measurable disease or tumor progression after surgery.
18.104.22.168 Patients unable to undergo MR imaging because of non-compatible devices can be enrolled, provided CT scans are obtained and are of sufficient quality. Patients without non-compatible devices may not have CT scans performed to meet this requirement.
3.1.4 History/physical examination within 14 days prior to registration;
3.1.5 Karnofsky Performance Scale >= 70 (Appendix II) within 14 days prior to registration;
3.1.6 Age >= 18;
3.1.7 Patients who have received prior treatment with interstitial brachytherapy, stereotactic radiosurgery, or implanted chemotherapy sources, such as wafers of polifeprosan 20 with carmustine, must have confirmation of progressive disease within 14 days prior to registration based upon nuclear imaging, MR spectroscopy, perfusion imaging or histopathology.
3.1.8 Patients must have normal organ and bone marrow function within 14 days prior to registration, as defined below:
* Leukocytes > 3,000 cells/mm3
* Absolute neutrophil count (ANC) >= 1,500 cells/mm3;
* Hemoglobin >= 10.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb >= 10.0
g/dl is acceptable.);
* Platelets >= 100,000 cells/mm3
Bilirubin <= 2.0 mg/dl;
* Creatinine within normal institutional upper limits or creatinine clearance > 60 mL/min/1.73 m2 (per 24
hour urine collection or calculated according to the Cockcroft-Gault formula) for subjects with
creatinine levels above the institutional normal; Patients with creatinine levels below normal institutional limits are eligible.
* Prothrombin time/international normalized ratio (PT INR) <= 1.5
* Urinary protein <= 30 mg/dl in urinalysis or <= 1+ on dipstick.
3.1.9 Generally well-controlled blood pressure with systolic blood pressure <= 140 mmHg AND diastolic blood pressure <= 90 mmHg within 5 days prior to registration. The use of anti-hypertensive medications to control hypertension is permitted (See Section 9).
3.1.10 Women of childbearing potential must have a negative serum [BETA]-HCG pregnancy test within 14 days prior to registration.
3.1.11Women of childbearing potential and male patients who are sexually active must practice adequate contraception during therapy and for 180 days (6 months) afterwards.
3.1.12 Patient must provide study specific informed consent prior to study entry.