Trial Information

A Phase III Randomized Study of Neuradiab in Combination With External Beam Radiation and Temozolomide Versus External Beam Radiation and Temozolomide in Patients With Newly Diagnosed Glioblastoma Multiforme

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).