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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

¹ Department of Surgery, The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina; ² Department of Pediatrics, The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina; ³ Department of Medicine, The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina; ⁴ Department of Radiology, The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina; ⁵ Cancer Center Biostatistics, The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina; and ⁶ Department of Pathology, The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina

Correspondence: For correspondence or reprints contact: David A. Reardon, MD, Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Box 3624, Durham, NC 27710. E-mail: reard003{at}mc.duke.edu

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 ¹³¹I-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 ¹³¹I-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). ¹³¹I-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 ¹³¹I-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 ¹³¹I-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. Conclusion: The MTD of ¹³¹I-ch81C6 is 2.96 GBq (80 mCi) because of dose-limiting hematologic toxicity. Although encouraging survival was observed, ¹³¹I-ch81C6 was associated with greater hematologic toxicity, probably due to the enhanced stability of the IgG2 construct, than previously observed with ¹³¹I-murine 81C6.

Key Words: radioimmunotherapy • monoclonal antibody • malignant glioma • glioblastoma multiforme • brain neoplasms

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				M. R. Zalutsky, D. A. Reardon, G. Akabani, R. E. Coleman, A. H. Friedman, H. S. Friedman, R. E. McLendon, T. Z. Wong, and D. D. Bigner Clinical Experience with {alpha}-Particle Emitting 211At: Treatment of Recurrent Brain Tumor Patients with 211At-Labeled Chimeric Antitenascin Monoclonal Antibody 81C6 J. Nucl. Med., January 1, 2008; 49(1): 30 - 38. [Abstract] [Full Text] [PDF]