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Neuro-Oncology 2005 7(3):246-253; doi:10.1215/S1152851704000869
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© 2005 by the Society forNeuro-Oncology

Phase 2 trial of copper depletion and penicillamine as antiangiogenesistherapy of glioblastoma

Steven Brem3, Stuart A. Grossman, Kathryn A. Carson, Pamela New, Surasak Phuphanich, Jane B. Alavi, Tom Mikkelsen, Joy D. Fisher for the New Approaches to Brain Tumor Therapy CNS Consortium

Department of Interdisciplinary Oncology andNeurosurgery, University of South Florida College of Medicine andNeuro-Oncology Program, H. Lee Moffitt Cancer Center, Tampa, FL 33620(S.B.); Department of Neuro-Oncology, The SidneyKimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231(S.A.G., K.A.C., J.D.F.); Department of Neurosurgery,Baylor College of Medicine, Houston, TX 77030 (P.N.); Department of Hematology-Oncology, Winship CancerInstitute, Emory University, Atlanta, GA 30322 (S.P.); Department of Hematology/Oncology, Hospital of theUniversity of Pennsylvania, Philadelphia, PA (J.B.A.); Department of Neurosurgery, Henry Ford Health System,Detroit, MI 48202 (T.M.); USA

3 Address correspondence to Steven Brem, c/o the NABTT CNS Consortium, 1650Orleans St., Room G-93, Baltimore, MD 21231, USA(brem{at}moffitt.usf.edu).


  Abstract

Penicillamine is an oral agent used to treat intracerebral copper overloadin Wilson's disease. Copper is a known regulator of angiogenesis; copperreduction inhibits experimental glioma growth and invasiveness. This studyexamined the feasibility, safety, and efficacy of creating a copper deficiencyin human glioblastoma multiforme. Forty eligible patients with newly diagnosedglioblastoma multiforme began radiation therapy (6000 cGy in 30 fractions) inconjunction with a low-copper diet and escalating doses of penicillamine.Serum copper was measured at baseline and monthly. The primary end point ofthis study was overall survival compared to historical controls within theNABTT CNS Consortium database. The 25 males and 15 females who were enrolledhad a median age of 54 years and a median Karnofsky performance status of 90.Surgical resection was performed in 83% of these patients. Normal serum copperlevels at baseline (median, 130 µg/dl; range, 50-227 µg/dl) fell to thetarget range of <50 µg/dl (median, 42 µg/dl; range, 12-118 µg/dl)after two months. Penicillamine-induced hypocupremia was well tolerated formonths. Drug-related myelosuppression, elevated liver function tests, and skinrash rapidly reversed with copper repletion. Median survival was 11.3 months,and progression-free survival was 7.1 months. Achievement of hypocupremia didnot significantly increase survival. Although serum copper was effectivelyreduced by diet and penicillamine, this antiangiogenesis strategy did notimprove survival in patients with glioblastoma multiforme.

Received September 14, 2004; Accepted January 11, 2005


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