title: 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.
abstract: OBJECTIVE
  Cintredekin besudotox (CB), a recombinant cytotoxin consisting of interleukin-13 and truncated Pseudomonas exotoxin, binds selectively to interleukin-13R alpha2 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 microg/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 microg/mL CB + EBRT [n = 3] and 0.25 microg/mL CB + EBRT + temozolomide [n = 3]). One patient experienced a dose-limiting toxicity (Grade 4 seizure) in the third cohort (0.5 microg/mL CB + EBRT [n = 6]). Six patients in the final cohort (0.5 microg/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.
  
  
  CONCLUSIONS
  CB (0.5 microg/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.
authors: Brain Tumor and Neuro-Oncology Center, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA. vogelbm@neus.ccf.org
authors: Michael A
authors: MA
authors: Vogelbaum
authors: John H
authors: JH
authors: Sampson
authors: Sandeep
authors: S
authors: Kunwar
authors: Susan M
authors: SM
authors: Chang
authors: Mark
authors: M
authors: Shaffrey
authors: Anthony L
authors: AL
authors: Asher
authors: Frederick F
authors: FF
authors: Lang
authors: David
authors: D
authors: Croteau
authors: Kristen
authors: K
authors: Parker
authors: Amy Y
authors: AY
authors: Grahn
authors: Jeffrey W
authors: JW
authors: Sherman
authors: S Rafat
authors: SR
authors: Husain
authors: Raj K
authors: RK
authors: Puri
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D017024:Chemotherapy, Adjuvant / Q000379:methods; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods; D005098:Exotoxins / Q000008:administration & dosage* / Q000009:adverse effects*; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000532:radiotherapy*; D006801:Humans; D036502:Infusions, Intralesional / Q000379:methods; D018793:Interleukin-13 / Q000008:administration & dosage* / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D009422:Nervous System Diseases / Q000139:chemically induced; D020266:Radiotherapy, Conformal; D011993:Recombinant Fusion Proteins; D000077204:Temozolomide; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D005098:Exotoxins; C521502:IL13-PE38; D018793:Interleukin-13; D011993:Recombinant Fusion Proteins; D003606:Dacarbazine; D000077204:Temozolomide