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.
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.
Reardon
David A
DA
Department of Surgery, The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina, USA. reard003@mc.duke.edu
Quinn
Jennifer A
JA
Akabani
Gamal
G
Coleman
R Edward
RE
Friedman
Allan H
AH
Friedman
Henry S
HS
Herndon
James E
JE
McLendon
Roger E
RE
Pegram
Charles N
CN
Provenzale
James M
JM
Dowell
Jeannette M
JM
Rich
Jeremy N
JN
Vredenburgh
James J
JJ
Desjardins
Annick
A
Sampson
John H
JH
Gururangan
Sridharan
S
Wong
Terence Z
TZ
Badruddoja
Michael A
MA
Zhao
Xiao-Guang
XG
Bigner
Darell D
DD
Zalutsky
Michael R
MR
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
C511833:(131)I-ch81C6; D000911:Antibodies, Monoclonal; D019275:Radiopharmaceuticals