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.
Brain Tumor and Neuro-Oncology Center, The Cleveland Clinic Foundation, Cleveland, Ohio (Vogelbaum) Department of Neurosurgery, Duke University, Durham, North Carolina (Sampson) Department of Neurosurgery, University of California, San Francisco, San Francisco, California (Kunwar) (Chang) Department of Neurosurgery, University of Virginia, Charlottesville, Virginia (Shaffrey) Carolina Neurosurgery and Spine Associates, Charlotte, North Carolina (Asher) Department of Neurosurgery, MD Anderson Cancer Center, Houston, Texas (Lang) NeoPharm Inc., Waukegan, Illinois (Croteau) (Parker) (Grahn) (Sherman) Center for Biologics Evaluation and Research, United States Food and Drug Administration, Bethesda, Maryland (Husain) (Puri).
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.
PMID: 18091279 [PubMed - as supplied by publisher]
