Scientific Publications by FDA Staff

Neurosurgery 2007 Nov;61(5):1031-8

Convection-enhanced delivery of cintredekin besudotox (interleukin-13-PE38QQR) followed by radiation therapy with and without temozolomide in newly diagnosed malignant gliomas: phase 1 study of final safety results.

Vogelbaum MA, Sampson JH, Kunwar S, Chang SM, Shaffrey M, Asher AL, Lang FF, Croteau D, Parker K, Grahn AY, Sherman JW, Husain SR, Puri RK

Vogelbaum MA (reprint author), Cleveland Clin Fdn, Brain Tumor & Neurooncol Ctr, 9500 Euclid Ave, Cleveland, OH 44195 USA Cleveland Clin Fdn, Brain Tumor & Neurooncol Ctr, Cleveland, OH 44195 USA Duke Univ, Dept Neurosurg, Durham, NC USA Univ Calif San Francisco, Dept Neurosurg, San Francisco, CA 94143 USA Univ Virginia, Dept Neurosurg, Charlottesville, VA USA Carolina Neurosurg & Spine Assoc, Charlotte, NC USA MD Anderson Canc Ctr, Dept Neurosurg, Houston, TX USA NeoPharm Inc, Waukegan, IL USA US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA

OBJECTIVE: Cintredekin besudotox (CB), a recombinant cytotoxin consisting of interleukin-13 and truncated Pseudomonas exotoxin, binds selectively to interleukin-13Ralpha2 receptors overexpressed by malignant gliomas. This study assessed the safety of CB administered by convection-enhanced delivery followed by standard external beam radiation therapy (EBRT) with or without temozolomide (Temodar; Schering-Plough, Kenilworth, NJ) in patients with newly diagnosed malignant gliomas. METHODS: After gross total resection of the tumor, two to four intraparenchymal catheters were stereotactically placed and CB (0.25 or 0.5 mug/mL) was infused for 96 hours. This was followed, 10 to 14 days later, by EBRT (5940-6100 cGy, 5 d/wk for 6-7 wk) with or without temozolomide (75 mg/m/d, 7 d/wk during EBRT). Safety was assessed during an 11-week observation period after catheter placement RESULTS: Twenty-two patients (12 men, 10 women; median age, 55 yr; 21 with glioblastoma multiforme and one with an anaplastic mixed oligoastrocytoma) were enrolled. None of the patients experienced dose-limiting toxicities in the first two cohorts (0.25 mug/mL CB + EBRT [n = 3] and 0.25 mug/mL CB + EBRT + temozolomide [n = 3]). One patient experienced a dose-limiting toxicity (Grade 4 seizure) in the third cohort (0.5 mug/mL CB + EBRT [n = 6]). Six patients in the final cohort (0.5 mug/mL CB + EBRT + temozolomide [n = 10]) completed treatment, and one patient experienced a dose-limiting toxicity (Grade 3 aphasia and confusion). Four patients were not considered evaluable for a dose decision and were replaced. CB related adverse events occurring in more than one patient were fatigue, gait disturbance, nystagmus, and confusion. No Grade 3 to 4 hematological toxicities were observed. CONCLUSION: CB (0.5 mug/mL) administered via convection-enhanced delivery before standard radiochemotherapy seems to be well tolerated in adults with newly diagnosed malignant gliomas. Further clinical study assessment is warranted.