David A. Reardon, MD

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Services

• Brain Tumors

Department / Division:
Surgery / Neurosurgery

Address:
DUMC 3624
Durham, NC 27710

Appointment Telephone:
(919) 684-3457

Office Telephone:
(919) 684-5301

Fax Telephone:
(919) 684-6674

• M.D., Tufts University School of Medicine, Massachusetts, 1986

• Pediatrics, Johns Hopkins Hospital, Department of Pediatrics, Maryland, 1986-1987, 1987-1989

• Pediatric Hematology/Oncology, University of Michigan Hospital, Mott Children's Hospital, Michigan, 1989-1992

Clinical Interests:
Design and implementation of clinical trials with innovative agents for patients with primary CNS tumors

Research Interests:
My primary clinical research responsibility at the Brain Tumor Center at Duke University Medical Center is as principal investigator for clinical trials incorporating the monoclonal antibody (Mab) 81C6. 81C6 was developed at Duke in the laboratory of Dr. Darell Bigner and targets the brain tumor-specific antigen, tenascin-C. The results of our extensive preclinical and clinical studies with 81C6 validate the effectiveness and safety of administering a radiolabeled Mab for patients with malignant brain tumors. To date, over 250 patients have been enrolled on seven completed and eight ongoing phase I and II trials incorporating radiolabeled murine 81C6. In our recently completed phase II study, patients with newly diagnosed GBM had a 35-50% longer median survival following 131I-labeled 81C6 compared to patients treated with conventional radiotherapy and chemotherapy alone or with the implantation of chemotherapy-impregnated wafers, even after accounting for established prognostic factors.  In addition, our studies demonstrate that 131I-labeled 81C6 therapy is much less toxic than other therapies "boosting" radiation delivery to the tumor bed resection cavity such as stereotactic radiosurgery or 125I interstitial brachytherapy. Based on these encouraging results, we developed a human/mouse chimeric 81C6 (ch81C6) in order to increase Mab stability and overall efficacy.  At present we have completed a phase I trial with 131I-labeled ch81C6 for patients with newly diagnosed and previously untreated malignant brain tumors and have moved forward with a phase II study in these patients.  In addition we have nearly completed phase I studies with 131I-labeled ch81C6 for patients with malignant brain tumors that are either newly diagnosed following external beam radiotherapy or recurrent.  Patient accrual also continues onto a phase I study using astatine-211-labeled ch81C6 for patients with recurrent primary or metastatic brain tumors. The latter clinical trial is the first to incorporate the alpha-emitting radioisotope astatine-211 (211At). Alpha-emitting radioisotopes may more effectively improve local tumor control than beta-emitting isotopes (such as 131I) because of their significantly shorter particle range, but much greater linear energy transfer.

Based on the highly encouraging results of clinical trials with radiolabeled 81C6 to date, the following three additional clinical trials are either under review or approved by the Duke IRB and therefore anticipated to open imminently:

1. Phase II Study of 131I -Labeled Anti-tenascin Murine Monoclonal Antibody 81C6 (mu81C6) Administered to Deliver a Targeted Radiation Boost Dose of 44 Gy to the Surgically Created Cystic Resection Cavity Perimeter in the Treatment of Patients with Newly Diagnosed Primary and Metastatic Brain Tumors.
The rationale for this protocol is based on our determination that patients who achieved a targeted delivery of 44 Gy to the resection cavity wall by 131I 81C6 had a lower rate of tumor recurrence than patients who achieved a lower delivered radiation dose.

2. Phase I Study of 211At-Labeled Anti-tenascin Human/Mouse Chimeric Monoclonal Antibody 81C6 (ch81C6) via Surgically Created Cystic Resection Cavity in the Treatment of Patients with Newly Diagnosed Primary and Metastatic Brain Tumors.
This protocol extends our experience with the alpha-emitting radioisotope astatine-211 to newly diagnosed patients and is designed to determine the maximum tolerated dose among such patients.

3. Phase I Study of 131I-Labeled Anti-tenascin Human/Mouse Chimeric Monoclonal Antibody  81C6 (ch81C6) F(ab')2 Fragment via Surgically Created Cystic Resection Cavity in the Treatment of Patients with Recurrent Malignant Brain Tumors.
F(ab')2 fragments are enzymatically derived products from intact Ig molecules that retain the antigen-binding variable region, but lack the constant region.  The smaller size of this Mab fragment is predicted to improve tumor penetration and increase systemic clearance resulting in overall greater efficacy and lower systemic toxicity.

In addition to serving as PI for the radiolabeled Mab protocols offered by the Brain Tumor Center at Duke, I am also PI or co-investigator on many of our center's additional phase I and II protocols designed to implement innovative therapeutic strategies such as: targeting novel tumor-specific factors including components of signal transduction pathways, angiogenic factors or modulators of tumor cell migration and adhesion; overcoming chemoresistance; defining more effective cytotoxic agents or combinations of agents; utilizing innovative drug delivery approaches such as bulk flow microinfusion; and establishing the role of immunotherapy against malignant brain tumors.

Representative Publications:
Reardon DA, Sublett JE, Ragsdale ST, Jenkins JE, Thompson S, Merchant T, Kun LE, Burger PC. Multiple genomic alterations including N-myc amplification in a primary large-cell medulloblastoma. Pediatr Neurosurg 32:187-191;2000. (2000)

Reardon DA, Akabani G, Coleman RE, Friedman AH, Friedman HS, Herndon JE, II, Cokgor I, McLendon RE, Pegram CN, Provenzale JM, Quinn JA, Rich J, Regalado LV, Sampson JH, Shafman TD, Wikstrand CJ, Wong TZ, Zhao X-G, Zalutsky MR, and Bigner DD. Phase II trial results of murine 131I-labeled anti-tenascin monoclonal antibody 81C6 administered into surgically created resection cavities of patients with newly diagnosed malignant gliomas. Accepted, J Clin Oncol, 2001. (2001)

Reardon D, Michalkiewicz E, Boyett J, Sublett J, Entrekin R, Ragsdale S, Valentine M, Behm F, Li H, Heideman R, Kun L, Shapiro D, Look A. Extensive genomic abnormalities in childhood medulloblastoma by comparative genomic hybridzation. Cancer Res 57:4042-4047, 1997. (1997)

Reardon D, Entrekin B, Sublett J, Ragsdale S, Li H, Boyett J, Look A. Chromosome 6q loss is the most common recurrent autosomal alteration detected in primary pediatric ependymoma. Genes, Chromosomes Cancer 24:230-237, 1999. (1999)

Reardon D, Gajjar A, Sanford R, Heideman R, Walter A, Thompson S, Boyett J, Li H, Jenkins J, Langston J, Kun L. Bithalamic involvement predicts a poor outcome among children with thalamic glial tumors. Pedatr Neurosurg 29:29-35, 1998. (1998)