• The primary measure of efficacy is overall survival (OS). [ Time Frame: Death from any cause ] [ Designated as safety issue: No ]
  

• Progression-free survival (PFS) is the sole secondary measure of efficacy. [ Time Frame: Difference between the date of randomization and the first date of meeting objective criteria for disease progression or death, whichever event is earliest. ] [ Designated as safety issue: No ]
  

In all cases where surgery is a possibility, tumor removal is usually indicated as the first step of therapy for glioblastomas. The goals of such surgery include removal of as much tumor mass as possible and preparation of the tumor bed for adjuvant therapy. Except for deaths arising from adverse surgical events (about 1-2% of surgeries), tumor removal enhances survival times. Unfortunately, without additional therapies, most GBM will recur at or near the original tumor site within several months. Addition of radiotherapy to surgery as part of the treatment regimen enhances survival in most patients compared to surgery alone.

The use and benefits of adjuvant chemotherapy for GBM is controversial. Some studies suggest an enhancement of survival from the use of agents such as carmustine (BCNU) and cisplatin, but generally only about 10-20% of the patient population shows such responses (Stewart 2002). The blood-brain barrier presents a major obstacle to traditional uses of chemotherapy in GBM, and, therefore, some clinical trials are focused on delivery of such agents directly to the brain/tumor mass via catheters with pressure-driven infusion.

At present, only two pharmacologic therapies are approved for the treatment of GBM, Gliadel® and Temodar®. Implantation of BCNU-impregnated wafers (Gliadel Wafer, Guilford Pharmaceuticals, approved by the U.S. Food and Drug Administration (FDA) in 1996) after surgery and radiotherapy was the first pharmacologic-chemotherapeutic therapy for GBM. It has shown very modest enhancements in overall survival (11.6 vs. 13.9 months) when added to a regimen of surgery and radiotherapy (Westphal et al. 2006). In this patient population, these agents demonstrate the typical side effects associated with antineoplastic chemotherapies, and are, therefore, often contraindicated. Nevertheless, despite FDA approval and availability of Gliadel for nearly a decade, its utility remains controversial and it is not routinely used in daily clinical practice. In 2005, the FDA approved the use of temozolomide (Temodar ®, Schering-Plough) given concurrently during and subsequent to radiotherapy for the treatment of newly diagnosed GBM. In a multicenter Phase III trial of 573 GBM patients, radiation alone gave a median survival rate of 12.1 months; the addition of temozolomide led to a median survival of 14.6 months (Stupp et al. NEJM 2005). More importantly, the 2-year survival rate increased from 10% with initial radiation alone to 27% with combined chemo- and radiotherapy. This regimen is considered the standard of care for all patients with newly diagnosed glioblastoma. Ongoing clinical trials are exploring alternative temozolomide administration schedules or combination of this regimen with novel chemotherapy or targeted anti-tumor agents assessing the efficacy of temozolomide alone or in various chemotherapeutic combinations are underway (Herrlinger et al. 2006, Mirimanoff et al. 2006, Stupp et al. 2006, Hau et. al. 2007).

The current study will investigate whether the addition of Neuradiab to surgery, radiation and adjuvant chemotherapy (temozolomide) will improve the survival of patients with glioblastoma and whether the drug regimen is safe. Earlier trials have demonstrated that patient-specific dosimetry yields the best combination of safety and efficacy and will be employed in the current trial. The anti-tenascin monoclonal antibody will bind to tenascin glycoprotein associated with residual neuroblastoma cells, causing the associated radioactive iodine to be fixed in close proximity to the tumor delivering cytocidal local radiotherapy. In this way, it is anticipated that residual tumor cells, which represent the primary reason for treatment failure using conventional therapy, will be destroyed, thus prolonging patient survival. The surgery, radiotherapy, and adjuvant chemotherapy will be administered to the patients in the control arm and represents appropriate therapy for this disorder. In addition, tumor samples will be analyzed for methyl guanine methyl transferase (MGMT) activity to see whether the previously observed and reported correlation with outcome is once again observed (Hegi et. al. 2005).