title: Novel human IgG2b/murine chimeric antitenascin monoclonal antibody construct radiolabeled with 131I and administered into the surgically created resection cavity of patients with malignant glioma: phase I trial results.
abstract: Results from animal experiments have shown that human IgG2/mouse chimeric antitenascin 81C6 (ch81C6) monoclonal antibody exhibited higher tumor accumulation and enhanced stability compared with its murine parent. Our objective was to determine the effect of these differences on the maximum tolerated dose (MTD), pharmacokinetics, dosimetry, and antitumor activity of (131)I-ch81C6 administered into the surgically created resection cavity (SCRC) of malignant glioma patients.
  
  
  METHODS
  In this phase I trial, eligible patients received a single injection of (131)I-ch81C6 administered through a Rickham catheter into the SCRC. Patients were stratified as newly diagnosed and untreated (stratum A), newly diagnosed after external beam radiotherapy (XRT) (stratum B), and recurrent (stratum C). (131)I-ch81C6 was administered either before (stratum A) or after (stratum B) conventional XRT for newly diagnosed patients. In addition, chemotherapy was prescribed for all patients after (131)I-ch81C6 administration. Dose escalation was performed independently for each stratum. Patients were observed for toxicity and response until death or progressive disease.
  
  
  RESULTS
  We treated 47 patients with (131)I-ch81C6 doses up to 4.44 GBq (120 mCi), including 35 with newly diagnosed tumors (strata A and B) and 12 with recurrent disease (stratum C). Dose-limiting hematologic toxicity defined the MTD to be 2.96 GBq (80 mCi) for all patients, regardless of treatment strata. Neurologic dose-limiting toxicity developed in 3 patients; however, none required further surgery to debulk radiation necrosis. Median survival was 88.6 wk and 65.0 wk for newly diagnosed and recurrent patients, respectively.
  
  
  CONCLUSIONS
  The MTD of (131)I-ch81C6 is 2.96 GBq (80 mCi) because of dose-limiting hematologic toxicity. Although encouraging survival was observed, (131)I-ch81C6 was associated with greater hematologic toxicity, probably due to the enhanced stability of the IgG2 construct, than previously observed with (131)I-murine 81C6.
authors.affiliation: Department of Surgery, The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina, USA. reard003@mc.duke.edu
authors.forename: David A
authors.initials: DA
authors.lastname: Reardon
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Quinn
authors.forename: Gamal
authors.initials: G
authors.lastname: Akabani
authors.forename: R Edward
authors.initials: RE
authors.lastname: Coleman
authors.forename: Allan H
authors.initials: AH
authors.lastname: Friedman
authors.forename: Henry S
authors.initials: HS
authors.lastname: Friedman
authors.forename: James E
authors.initials: JE
authors.lastname: Herndon
authors.forename: Roger E
authors.initials: RE
authors.lastname: McLendon
authors.forename: Charles N
authors.initials: CN
authors.lastname: Pegram
authors.forename: James M
authors.initials: JM
authors.lastname: Provenzale
authors.forename: Jeannette M
authors.initials: JM
authors.lastname: Dowell
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Rich
authors.forename: James J
authors.initials: JJ
authors.lastname: Vredenburgh
authors.forename: Annick
authors.initials: A
authors.lastname: Desjardins
authors.forename: John H
authors.initials: JH
authors.lastname: Sampson
authors.forename: Sridharan
authors.initials: S
authors.lastname: Gururangan
authors.forename: Terence Z
authors.initials: TZ
authors.lastname: Wong
authors.forename: Michael A
authors.initials: MA
authors.lastname: Badruddoja
authors.forename: Xiao-Guang
authors.initials: XG
authors.lastname: Zhao
authors.forename: Darell D
authors.initials: DD
authors.lastname: Bigner
authors.forename: Michael R
authors.initials: MR
authors.lastname: Zalutsky
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001822:Body Burden; D001932:Brain Neoplasms / Q000378:metabolism* / Q000532:radiotherapy*; D004307:Dose-Response Relationship, Radiation; D005260:Female; D005910:Glioma / Q000378:metabolism* / Q000532:radiotherapy*; D006801:Humans; D015552:Injections, Intralesional; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D008875:Middle Aged; D011874:Radiometry; D019275:Radiopharmaceuticals / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D011879:Radiotherapy Dosage; D015996:Survival Rate; D014018:Tissue Distribution; D016896:Treatment Outcome
chemical_list: C511833:(131)I-ch81C6; D000911:Antibodies, Monoclonal; D019275:Radiopharmaceuticals