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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

Phase 3
18 Years
Not Enrolling
Glioblastoma Multiforme

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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).

Inclusion Criteria:

- Newly diagnosed supratentorial unifocal lesion seen on magnetic resonance imaging

- Patient must have undergone a gross total surgical resection of the tumor mass with
post surgical MRI (performed within 14 days of randomization) demonstration of
adequacy defined as < 1.0 cm of residual enhancement away from resection cavity

- Histopathologically confirmed diagnosis of glioblastoma (World Health Organization
[WHO] grade IV astrocytoma) and tumor sample is available.

- Age ≥ 18 years of age at the time of study entry.

- Karnofsky Performance Status ≥ 60%.

- Adequate bone marrow function, defined as:

1. Absolute neutrophil count ≥ 1500 cells/mm3

2. Hemoglobin ≥ 10 g/dL

3. Platelet count ≥ 100,000 cells/mm3

- Adequate hepatic function, defined as:

1. Bilirubin ≤ 1.5 mg/dL

2. SGOT ≤ 2.5 × upper limit of normal (ULN

- Adequate renal function, defined as creatinine ≤ 1.3 mg/dL (µmol/L)

- Patients must have a negative HAMA (human anti-murine antibody) assay.

- Women of childbearing potential must have a negative pregnancy test (serum or urine).

- Men and women of reproductive potential must agree to use an effective contraceptive
method including one of the following: surgical sterilization (tubal ligation for
women or vasectomy for men); approved hormonal contraceptives (such as birth control
pills, Depo-Provera or Lupron Depro); barrier methods (such as condom or diaphragm)
used with a spermicide cream or an intrauterine device (IUD).

- Patient must give written informed consent prior to any study-specific procedures
being implemented.

Exclusion Criteria:

- Infratentorial tumor, tumor with subependymal spread, multifocal tumor, tumor with
ventricular communication, intraventricular tumor or tumor which abuts the motor
strip or exceeds beyond the cranial vault.

- Pregnant or lactating females.

- Women of childbearing potential and men who are sexually active and not willing/able
to use medically acceptable forms of contraception.

- No severe, active comorbidity, including any of the following:

1. Unstable angina and/or congestive heart failure requiring hospitalization

2. Transmural myocardial infarction within the last 6 months

3. Acute bacterial or fungal infection requiring intravenous antibiotics at the
time of randomization

4. Chronic obstructive pulmonary disease exacerbation or other respiratory illness
requiring hospitalization or precluding study therapy at the time of

5. Known hepatic insufficiency resulting in clinical jaundice and/or coagulation

6. Known AIDS based upon current CDC definition

7. Major medical illnesses or psychiatric impairments that, in the investigator's
opinion, will prevent administration or completion of protocol therapy

8. Active connective tissue disorders, such as lupus or scleroderma that, in the
opinion of the treating physician, may put the patient at high risk for
radiation toxicity.

- Prior or planned chemotherapy, immunotherapy, biologic therapy, radiation therapy,
radioimmunotherapy, hormonal therapy, or experimental therapy for brain tumor. Prior
or active corticosteroid therapy is permitted.

- History of severe allergic reaction to contrast media.

- Any serious medical condition or psychiatric illness unresponsive to medical

- Prior malignancy if active treatment was required during the previous 3 years except
for adequately treated basal cell or squamous cell skin cancer and in situ uterine
cervical cancer.

- Known hypersensitivity to murine proteins.

- Inability to undergo an MRI.

- Patients treated on any other therapeutic clinical trial within 30 days prior to
study entry or during participation in the study.

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

The primary measure of efficacy is overall survival (OS).

Outcome Time Frame:

Death from any cause

Safety Issue:


Principal Investigator

David A. Reardon, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Duke University


United States: Food and Drug Administration

Study ID:




Start Date:

June 2008

Completion Date:

December 2013

Related Keywords:

  • Glioblastoma Multiforme
  • Neuradiab
  • Locoregional glioblastoma multiforme disease
  • Anti-tenascin
  • Radiolabeled antibody therapy
  • Survival
  • Glioblastoma