Phase 2 trial of copper depletion and penicillamine as antiangiogenesis therapy of glioblastoma

Abstract

Penicillamine is an oral agent used to treat intracerebral copper overload in Wilson's disease. Copper is a known regulator of angiogenesis; copper reduction inhibits experimental glioma growth and invasiveness. This study examined the feasibility, safety, and efficacy of creating a copper deficiency in human glioblastoma multiforme. Forty eligible patients with newly diagnosed glioblastoma multiforme began radiation therapy (6000 cGy in 30 fractions) in conjunction with a low-copper diet and escalating doses of penicillamine. Serum copper was measured at baseline and monthly. The primary end point of this study was overall survival compared to historical controls within the NABTT CNS Consortium database. The 25 males and 15 females who were enrolled had 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 copper levels at baseline (median, 130 microg/dl; range, 50-227 microg/dl) fell to the target range of <50 microg/dl (median, 42 microg/dl; range, 12-118 microg/dl) after two months. Penicillamine-induced hypocupremia was well tolerated for months. Drug-related myelosuppression, elevated liver function tests, and skin rash rapidly reversed with copper repletion. Median survival was 11.3 months, and progression-free survival was 7.1 months. Achievement of hypocupremia did not significantly increase survival. Although serum copper was effectively reduced by diet and penicillamine, this antiangiogenesis strategy did not improve survival in patients with glioblastoma multiforme.

Figures

Fig. 1

Overall survival (Kaplan-Meier curves) for penicillamine study (solid line) compared to other NABTT trials of treatment concurrent with RT (broken line).

Fig. 2

Overall survival (Kaplan-Meier curves) for patients achieving low copper by three months (solid line) compared to those that did not (broken line).

Fig. 3

Hypocupremia achieved after penicillamine therapy. The dashed line represents the targeted serum copper level of 50 μg/dl. The solid line connects the median levels from each monthly visit for the patients that were sampled. At the baseline visit (month 0) data were available on 36 patients. At month 6, only 15 patients